Compositions, methods of treatment and diagnostics for treatment of hepatic steatosis alone or in combination with a Hepatitis C virus infection

ABSTRACT

The present invention is directed to pharmaceutical compositions and methods of treatment that relate to the inhibition, resolution and/or prevention of an array of the manifestations of metabolic syndromes, including Type 2 diabetes, hyperlipidemia, weight gain, obesity, insulin resistance, hypertension, atherosclerosis, fatty liver diseases and certain chronic inflammatory states that lead to these manifestations, among others. In additional aspects, the present invention relates to compositions and methods which may be used to treat, inhibit or reduce the likelihood of hepatitis viral infections, including Hepatitis B and Hepatitis C viral infections, as well as the secondary disease states and/or conditions which are often associated with such viral infections, including hepatic steatosis (steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer, among other disease states or conditions.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 14/002,642,filed Aug. 30, 2013, of identical title, now U.S. Pat. No. 9,370,528,issued Jun. 21, 2016, which claims the benefit of priority of and is aUnited States national phase application of International PatentApplication Number PCT/US2012/026561 filed in the United StatesReceiving Office on Feb. 24, 2012, which is a continuation in partclaiming the benefit of priority of U.S. patent application Ser. No.12/932,633 filed Mar. 2, 2011, entitled “Compositions and Methods forInducing Satiety and Treating Non-Insulin Dependent Diabetes Mellitus,Prediabetic Symptoms, Insulin Resistance and Related Disease States andConditions, which claims the benefit of priority of provisionalapplication Ser. No. 61/309,991, filed Mar. 3, 2010, entitled“Compositions and Methods for Inducing Satiety and Treating Non-InsulinDependent Diabetes Mellitus, Pre-diabetic symptoms, Insulin Resistanceand Related Disease States and Conditions”. Patent Application NumberPCT/US2012/026561 also claims priority from provisional applicationsserial number U.S. 61/480,788, filed Apr. 29, 2011 entitled, “Long TermStimulation of Ileal hormones by an Orally Delivered, Ileal ReleasedNatural Product Aphoeline”, serial number U.S. 61/514,174, filed Aug. 2,2011, entitled, “Gut CFO: the ileal hormones. Decreasing insulinresistance, triglycerides, liver enzymes, signaling caloric intake,using caloric reserve, and turning body to health with every meal”, andserial number U.S. 61/551,638, filed Oct. 26, 2011, entitled “OralFormulations Mimetic of Roux-en-Y Gastric Bypass Actions on the IlealBrake; Compositions, Methods of Treatment, Diagnostics and Systems forTreatment of Metabolic Syndrome Manifestations, Including InsulinResistance, Fatty Liver Disease, Hyperlipidemia and Type 2 Diabetes,each of said aforementioned applications being incorporated by referencein their entirety herein.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions,methods of treatment, and diagnostics and computer-implementable systemsthat relate to the treatment of an array of the manifestations ofmetabolic syndromes, including Type 2 diabetes, hyperlipidemia, weightgain, obesity, insulin resistance, hypertension, atherosclerosis, fattyliver diseases and certain chronic inflammatory states that lead tothese manifestations, among others. In additional aspects, the presentinvention relates to compositions and methods which may be used totreat, inhibit or reduce the likelihood of hepatitis viral infections,including Hepatitis B and Hepatitis C viral infections, as well as thesecondary disease states and/or conditions which are often associatedwith such viral infections, including hepatic steatosis(steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer,among other disease states or conditions.

BACKGROUND OF THE INVENTION

Hepatitis C infects 2-3% of the world's population, over 180 millionpersons, and is a cause of chronic hepatitis, liver cirrhosis, andhepatocellular carcinoma (1). The current standard of care, pegylatedinterferon plus ribavirin (pegIFN/Riba) combination therapy, is bothexpensive and poorly tolerated. Treatment efficacy is approximately 50%.Telaprevir and boceprevir, two direct acting antiviral (DAA) proteaseinhibitors, have recently been approved for clinical use in the US (2).Addition of either of these new agents has the potential to improvesustained virological response in hepatitis C to 65-75%. However, theaddition of a DAA to the current standard of care introduces the risk ofside effects, including anemia and rash, and failure to achieveSustained viral response may pose an increased risk of accumulationprotease inhibitor-resistant viral strains that may carry overresistance problems to future treatments. None of these current orfuture treatments appear to provide any benefit to the patient beyondsuppression of the virus. Specifically, the liver is not healed evenwhen viral counts are very low, the damage either ceases at the point ofsuppression, or inflammation and fibrosis may even progress slowly inthe presence of a small number of residual viral particles. Hepaticsteatosis, the primary accompanying condition of most patients withhepatitis C, continues and may progress even with complete viralsuppression, and it is now time to propose that hepatic steatosis mustbe managed in lock step with the specific anti-viral treatments.

Hepatic steatosis is a common diagnosis in populations as a whole, oftenas frequent as 25% (3). There is no drug therapy for hepatic steatosisat the present time (4), most experts rely on lifestyle counselingalone. Of great concern, hepatic steatosis is a histologic feature inapproximately two thirds of liver biopsies of patients with chronichepatitis C. Until recently, this common finding was not carefullydocumented, and there were no large longitudinal studies describing theprogression of steatosis in chronic hepatitis C or even hepatitis B. In2009, Lok and colleagues examined changes in steatosis on serialbiopsies among chronic hepatitis C patients participating in theHepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C)trial (5). All 1050 patients in this trial had advanced fibrosis atbaseline biopsy and were documented not to have had a sustainedvirological response to pegIFN/Riba. Most (94%) of these patients hadgenotype 1 infection. At least one protocol follow-up biopsy was read on892 patients, and 699 had the last biopsy performed 3.5 years afterrandomization. Hepatic damage was well advanced at enrollment, as 39%had cirrhosis and 61% had bridging fibrosis; 18%, 41%, 31%, and 10% hadsteatosis scores of 0, 1, 2, and 3 or 4, respectively. The meansteatosis score decreased in the follow-up biopsies in both thepegIFN/Riba-treated patients and controls with no effect of treatmentassignment (P=0.66). A decrease in steatosis score by > or =1 point wasobserved in 30% of patients and was associated with both progression tocirrhosis and continued presence of cirrhosis (P=0.02). Compared topatients without a decrease in steatosis, those with a decrease insteatosis had worse metabolic parameters at enrollment, and were morelikely to have a decrease in alcohol intake, improvement in metabolicparameters, and worsening liver disease (cirrhosis, esophageal varices,and deterioration in liver function). Lok and colleagues (5) concludedthat hepatic steatosis recedes during progression from advanced fibrosisto cirrhosis. However, there was no available means to produce a declinein hepatic steatosis in most patients, which then became the primarymotivation to discover a means of treating hepatic steatosis as anintegral part of treatment of hepatitis C patients.

In a further definitive examination of the role of hepatic steatosis onthe course of hepatitis C therapy, Briceno and colleagues (2009)examined livers that were to be transplanted into patients withhepatitis C that had already destroyed the original liver (6). The aimof this study was to determine the influence of donor graft steatosis onoverall outcome, viral recurrence, and fibrosis progression inorthotopic liver transplantation for hepatitis C virus cirrhosis. Onehundred twenty patients who underwent OLT for HCV cirrhosis between 1995and 2005 were included in the study. Donor steatosis was categorized asabsent (0%-10%; n=40), mild (10%-30%; n=32), moderate (30%-60%; n=29),or severe (>60%; n=19). A Cox multivariate analysis for marginal donorvariables and a Model for End-Stage Liver Disease index were performed.Fibrosis evolution was analyzed in liver biopsies (fibrosis <2 or > or=2) 3, 6, and 12 months post-OLT and in the late post-OLT period.Fifty-six grafts were lost (46%). The survival of the grafts wasinversely proportional to donor liver steatosis: 82%, 72%, and 72% at 1,2, and 3 years post-OLT in the absence of steatosis; 73%, 63%, and 58%with mild steatosis; 74%, 62%, and 43% with moderate steatosis; and 62%,49%, and 42% with severe steatosis (P=0.012). HCV recurrence was earlierand more frequent in recipients with steatosis >30% (46% versus 32% at 3months, P=0.017; 58% versus 43% at 6 months, P=0.020; 70% versus 56% at12 months, P=0.058; and 95% versus 69% at 3 years post-OLT, P=0.0001).(6). Graft survival was lower in alcoholic liver disease recipientsversus HCV recipients when steatosis was >30% at 3, 6, and 12 monthspost-OLT (P=0.042) but not when steatosis was <30% (P=0.53). A higherfibrosis score was obtained 3 months post-OLT (P=0.033), 6 monthspost-OLT (P=0.306), 12 months post-OLT (P=0.035), and in the latepost-OLT period (P=0.009). The authors concluded that the degree ofhepatic steatosis in the new liver greatly influences the recurrence ofhepatitis C and its progression in the new liver. In fact, Steatosisaffects the success of treatment the second time. Hepatitis C recurrencewas more frequent and earlier in recipients of moderately and severelysteatotic livers. Fibrosis evolution is more rapid and severe when graftsteatosis is >30% (6). As pointed out by Lok as well, there is a need tomanage the hepatic steatosis in order to optimize the outcome ofantiviral therapy for hepatitis C.

Testino and colleagues (2009) examined the influence of improvement inmetabolic syndrome (typically associated with steatosis) biomarkers onthe response of patients with hepatitis C to pegIFN/Riba (7). Theyexamined baseline biomarkers such as Body Mass Index (BMI), cholesterol,triglycerides (TGs) and hepatic percentage of steatosis in the responseto therapy with pegIFN/Riba in patients with recurrent hepatitis C(genotype 1). In this study, 30 consecutive prospectively followedpatients diagnosed with recurrent hepatitis C were considered candidatesfor antiviral therapy. The observed distribution of BMI, cholesterol,TGs and steatosis were confirmed to be normally distributed by theone-sample Kolmogorov-Smirnov Goodness of fit test procedure. Comparisonof BMI, cholesterol, TGs and steatosis between non responders (NR),sustained virological responders (SVR) and sustained biochemicalresponders (SBR) groups were analyzed by ANOVA with a post hocBonferroni test and correlation between variables was tested by Pearsontest. The multivariate analysis was performed to estimate the chance ofresponse on basis of the above mentioned variables. In patients withabnormal results in at least two out of four steatosis associatedvariables the chance of no-response was 40 times higher than that of SBRand 96 times than that of SVR (7). On the basis of these epidemiologicalstudies, they argued that diet and exercise therapy should improve BMI,liver histology and, therefore, the response to pegIFN/Riba (7). Indeedthis study provides further justification for concomitant use of atreatment for hepatic steatosis in conjunction with a treatment for thehepatitis C virus itself.

There is also evidence that management of hepatic steatosis in patientswith hepatitis C would be of value in the prevention of hepatocellularcarcinoma (HCC). For example, Pekow and colleagues (2007) (8)retrospectively identified 94 consecutive patients with hepatitis Ccirrhosis who underwent liver transplantation from 1992 to 2005 and hadpathology available for review. Of these, 32 had evidence of HCC, and 62had no HCC on explant histology. All explant specimens were then gradedfor steatosis by a single, blinded pathologist. Next, hepatic steatosis,age, sex, BMI, HCV RNA, HCV genotype, Model for End-Stage Liver Disease(MELD) score, chronic alcohol use, and diabetes were examined inunivariate and multivariate analyses for association with HCC. In total,69% of patients in the HCC group and 50% of patients in the controlgroup had evidence of hepatic steatosis (1+) on histology. Odds ratiosfor the development of HCC for each grade of steatosis compared withgrade 0 were as follows: grade 1 (1.61 [0.6-4.3]), grade 2 (3.68[1.1-12.8]), and grade 3 or 4 (8.02 [0.6-108.3]) (P=0.03 for the trend).In univariate analyses, there was a significant association betweenincreasing steatosis grade (P=0.03), older age (56 years vs. 49 years;P<0.02), higher ALT aspartate aminotransferase (122.5 U/L vs. 91.5 U/L;P=0.005), higher AST alanine aminotransferase (95.8 U/L vs. 57.2 U/L;P=0.002), higher alpha-fetoprotein (113.5 ng/mL vs. 17.8 ng/mL;P<0.001), lower median HCV RNA (239,000 IU/mL vs. 496,500 IU/mL;P=0.02), higher biologic MELD score (21.8 vs. 20.3; P=0.03), and risk ofHCC. In multivariate analysis, age (P=0.02), alpha-fetoprotein(P=0.007), and hepatic steatosis (P=0.045) were significantly associatedwith HCC (8). These authors concluded that in patients with HepatitisC-related cirrhosis, the presence of hepatic steatosis is independentlyassociated with the development of hepatocellular carcinoma (8). Clearlyif the steatosis could be reversed, there is plausible evidence that HCCmight be prevented or at least there would be fewer cases that progressto this deadly complication of the combined problem of hepatitis C andhepatic steatosis.

BRIEF DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to pharmaceuticalcompositions, methods for the treatment, and diagnostics andcomputer-implementable systems that relate to the treatment of an arrayof the manifestations of metabolic syndromes, including Type 2 diabetes,hyperlipidemia, weight gain, obesity, insulin resistance, hypertension,atherosclerosis, fatty liver diseases and certain chronic inflammatorystates that lead to these manifestations.

In an additional aspect of the invention, compositions and methods oftreatment (which may entail concomitant pharmacological and/or surgicalintervention e.g. Roux-en-Y gastric bypass (RYGB)) activate the ilealbrake, which acts in the gastrointestinal tract and the liver of amammal to control metabolic syndrome manifestations and thereby reverseor ameliorate the cardiovascular damage (atherosclerosis, hypertension,lipid accumulation, and the like) resulting from progression ofmetabolic syndrome. These compositions and/or methods may be used aloneor in combination with additional bioactive agents, especially includinganti-viral agents such as anti-hepatitis viral agents, especiallyanti-HCV agents and/or anti-HBV agents to treat the virus which iscausing hepatitis as well as any secondary disease states and/orconditions which are caused by the viral infection. The effect of thepresent invention is synergistic in the patient or subject treated.

A primary target organ for improvement, reconstitution, orrehabilitation is the liver. The invention provides compositions,methods of treatment, diagnostics, and related systems useful instabilizing blood glucose and insulin levels, control of hyperlipidemia,control of inflammation in organs tissues and blood vessel walls.

The present invention is also directed to combination(co-administration) treatment for use in viral infections that causeinflammation in the liver and well as numerous secondary disease statesand/or conditions of the liver, including but not limited to HepatitisC, Hepatitis B, Herpes Simplex virus, as well as any virus that causesinjury to the mammal by causing inflammation and fibrotic changes in theliver. The effect of the present invention is synergistic. One aspect ofthis combination treatment consists of providing ileal brake hormonereleasing therapy in combination with an antiviral drug active againstthe virus itself. This may entail administering an ileal brake compound(ileal brake hormone releasing substance) or compositions in combinationwith a bioactive agent such as an antiviral and/or anticancer agent, oralternatively, providing a method which activates the ileal brake suchas a surgical intervention e.g. Roux-en-Y gastric bypass (RYGB)) incombination with the bioactive agent. The combination treatment of thepresent invention resolves the hepatic steatosis and thereby inhibits orotherwise reduces the likelihood of progressive injury to the liver thatresults from the fibrosis and cirrhosis, preferably in a synergisticmanner.

The present invention provides that effective anti-viral treatment,including a cure of the viral infection, requires a composition whichinhibits or otherwise treats the hepatic steatosis that is present innearly all of these patients. This anti hepatic steatosis treatment mustbe effectively combined with a treatment active against the virus toincrease the chances of both eradicating the virus and healing theinjured liver. Thus, the invention provides methods of treatment andpharmaceutical compositions that can be used to prevent, reduce thelikelihood of, or delay the onset of, a progressive damage to the liverwhich leads to cirrhosis, including fibrosis and related disease statesand conditions of the condition, including hepatic steatosis andcirrhosis. It is noted that hepatic steatosis may also progress tohepatocellular carcinoma in patients with concomitant hepatitis viralinfection, including hepatitis B and C virus infection. The combinationof the present pharmaceutical composition with the anti-viral medicationcan be used to prevent, reduce the likelihood of, or delay the onset of,hepatocellular carcinoma in patients with hepatitis B and hepatitis C.

In one particular aspect of the invention, a novel formulation ofglucose in dosages of approximately 10 grams or less per day, has bothshort and long term beneficial effects on patients with elevatedtriglycerides, insulin resistance and elevated liver enzymes indicativeof hepatic steatosis. Dietary glucose and other sugars increase themanufacture of triglycerides which are prominent among the causes offatty liver, and hepatic steatosis is an accessory pathway for viralreplication. Dietary lipids accumulate in the liver as well. It is arecent discovery that releasing these dietary substances at a distallocation in the intestine by the unique intestinal site targeted-releaseproperties of the present formulations, can ameliorate not only thehyperglycemic manifestations of Type 2 diabetes, but also to control theaccumulation of fat in the liver. These ileal brake compositionsaccording to the present invention, when administered to a patient inneed thereof, are useful to lower the patient's insulin resistance,lower triglycerides, reduce body weight, reduce HBA1c, and lower chronicliver inflammation (reduce ALT and AST), all in the manner similar toeffect of RYGB surgery.

By means of careful study of enabling biomarkers, it becomes clear theileal brake composition provides physiological and pharmaceuticalactions on the same anatomical location of the patient and affects thesame biochemical pathways as RYGB surgery, the biological target of bothbeing the L-cells of the ileum and distal intestine.

In alternative embodiments, the present invention relates tocompositions and methods useful for selective modulation of appetite ina manner similar to that of RYGB surgery. For example, the presentinvention also relates to ileal brake compositions (i.e., ileal brakehormone releasing substances), more particularly, a preferred oralformulation of ileal brake hormone releasing substances which contain acombination of carbohydrates and lipids, which are particularly adaptedto treating insulin resistance and fatty liver, and are synergistic withspecific anti-viral medicaments active against hepatitis viruses,including Hepatitis B and Hepatitis C viruses, among others.

Accordingly, the present invention also relates to a novel formulationand methods of treatment of disease states, disorders and/or conditions,or manifestations of hepatic steatosis, which is also known as fattyliver disease, non-alcoholic steatohepatitis (NASH) or non-alcoholicfatty liver disease (NAFLD). It should be added that there is nocurrently accepted pharmaceutical treatment for hepatic steatosisavailable, while it is acknowledged that both RYGB and the Brakeformulation encompass the widest array of beneficial treatment thus fardiscovered.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows that the hepatitis C viral count in a patient administereda composition according to the present invention decreased rapidly to100K.

FIG. 2 shows the effect on hepatic parameters after administration of anileal brake composition (formulation II) according to the presentinvention. Administration for six months shows a substantial impact onthree of the four hepatic parameters followed.

FIG. 3 shows the effect of Aphoeline II (Formulation II) added to treatHepatitis C, Genotype 1a TC, treated with Riba/PegIFN. The figure showsa substantial reducing in viral titer with a formulation according tothe present invention in combination with a standard therapeutic regimenof pegylated interferon and ribavirin.

FIG. 4 shows the effect on hepatic parameters of a patient who was puton a combination of formulation II in combination with pegylatedinterferon and ribavirin for a period of 24 months.

FIG. 5 shows effect on the weight of the patient from FIG. 4, above,after a period of 24 months. Note that the patient lost more than 20pounds during that period.

FIG. 6 shows effect of the ileal brake composition and viral combinationtherapy on alpha-fetoprotein after 24 months total therapy.

FIG. 7 shows the effect on Hepatitis C titers in a patient after 12months of therapy on the ileal brake composition (formulation II).

FIG. 8 shows the effect on alpha-fetoprotein on a patient (same patientas in FIG. 7) after 12 months of therapy on the ileal brake composition(formulation II).

FIG. 9 shows that liver enzymes also decline, consistent with thehealing, improvement in steatosis and the lowering of inflammation after12 months of therapy on the ileal brake composition (formulation II).

FIG. 10 shows a diagrammatic representation of a summary of the ilealbrake pathways, which clearly places the portal system and the liver atthe center of the regulatory organs in the diet and obesity axis. Whenthe ileal brake pathway is out of control and over-eating accelerates,these controlling hormonal pathways lead to metabolic syndromemanifestations such as obesity, fatty liver disease, andatherosclerosis. Fatty liver disease is a precursor of fibrosis,cirrhosis and even hepatocellular carcinoma.

DETAILED DESCRIPTION OF THE INVENTION

The following terms shall be used to describe the present invention. Ininstances where a term is not specifically defined herein, the termshall be accorded its meaning, within the context of its use, asunderstood by those of ordinary skill in the art.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

The term “patient” or “subject” is used throughout the specificationwithin context to describe an animal, generally a mammal, including adomesticated animal other than a laboratory animal (rat, mouse etc.) andpreferably a human, to whom treatment, including prophylactic treatment(prophylaxis), with the compositions according to the present inventionis provided. For treatment of those infections, conditions or diseasestates which are specific for a specific animal such as a human patient,the term patient refers to that specific animal.

The term “compound” shall mean any specific compound which is disclosedwithin this specification and typically means a single agent or apharmaceutically acceptable salt thereof, or a bioactive agent or drugas otherwise described herein, including pharmaceutically acceptablesalts thereof, generally a drug. Compounds are included in amountseffective to produce an intended physiological effect. Certain compoundsaccording to the present invention may be used to treat secondaryconditions such as type II diabetes, hepatic steatosis(steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer orto suppress the immune system in liver transplant patients, or to treatviral infections directly (e.g., hepatitis B and/or C) in order toreduce the likelihood of a condition occurring or to advance therapies.Pharmaceutically acceptable salts are also compounds for use in thepresent invention.

The term “effective” when used in context, shall mean any amount of acompound or component which is used to produce an intended result withinthe context of its use. In the case of bioactive agents according to thepresent invention, the term effective generally refers to atherapeutically effective amount of compound which will produce anintended physiological effect associated with that agent, generallyincluding antiviral activity. In the case of the treatment of hepatitis,hepatic steatosis (steatohepatitis), an effective amount of a compoundor composition and/or bioactive agent is that amount which is effectiveto treat the condition which is being treated by administering theagent.

The term “hepatitis” is used to describe a liver condition which impliesinjury to the liver characterized by the presence of inflammatory cellsin the tissue of the organ. The condition can be self-limiting, healingon its own, or can progress to scarring of the liver. Hepatitis is acutewhen it lasts less than six months and chronic when it persists longerthan six months. A group of viruses known as the hepatitis viruses isprincipally responsible for most cases of liver damage worldwide.Hepatitis may run a subclinical course when the affected person may notfeel ill. The patient becomes unwell and symptomatic when the diseaseimpairs liver functions.

Hepatitis includes hepatitis from viral infections, including HepatitisA through E (A, B, C, D and E—more than 95% of viral cause hepatitis,especially including hepatitis B and C), Herpes simplex,Cytomegalovirus, Epstein-Barr virus, yellow fever virus, adenoviruses;non-viral infections, including toxoplasma, Leptospira, Q fever androcky mountain spotted fever, as well as alcohol, toxins, includingamanita toxin in mushrooms, carbon tetrachloride, asafetida, amongothers, drugs, including paracetamol, amoxicillin, antituberculosismedicines, minocycline and numerous others as described herein.

The term “Hepatitis C Virus” or “HCV” is used to describe the variousstrains of Hepatitis C virus. HCV is one of several viruses that cancause hepatitis. It is unrelated to the other common hepatitis viruses(for example, hepatitis A or hepatitis B, among others). HCV is a memberof the Flaviviridae family of viruses. Other members of this family ofviruses include those that cause yellow fever and dengue. Virusesbelonging to this family all have ribonucleic acid (RNA) as theirgenetic material. All hepatitis C viruses are made up of an outer coat(envelope) and contain enzymes and proteins that allow the virus toreproduce within the cells of the body, in particular, the cells of theliver. Although this basic structure is common to all hepatitis Cviruses, there are at least six distinctly different strains of thevirus which have different genetic profiles (genotypes). Treatment ofHCV according to the present invention is directed to all strains ofHCV, including the six or more distinct strains described above, as wellas related strains which are drug resistant and multiple drug resistantstrains. In the U. S., genotype 1 is the most common form of HCV. Evenwithin a single genotype there may be some variations (genotype 1a and1b, for example). Genotyping is viewed as important to guide treatmentbecause some viral genotypes respond better to therapy than others. HCVgenetic diversity is one reason that it has been difficult to develop aneffective vaccine since the vaccine must protect against all genotypes.

A “Hepatitis C virus infection” or “Hepatitis C infection” is aninfection of the liver caused by the hepatitis C virus (HCV).

The term “synergy” or “synergistic” refers to an effect or result onviral inhibition and/or hepatic steatosis, cirrhosis and/orhepatocellular cancer as evidenced by hepatic function (e.g., viral loadin monitoring viral infection or a hepatic marker in monitoring hepaticsteatosis) which is greater than that which is or would expected from asimple combination of therapies, or providing a more rapid return tonormalcy, cure or cure rate. Thus, if one were to combine theadministration of an ileal brake compound with that of an antiviralcompound or compounds pursuant to the present invention, a synergisticresult is that result which is greater than the additive result onewould expect from combining the two therapies. A synergistic result fora particular compound or therapy is that result which occurs which isgreater than the additive result or effect one would expect from simplydoubling the dose of amount of a compound or composition used. By way ofexample (and not by limitation), for viral load reduction, additivelywill generally provide a 1 or 2 log reduction in viral titers, whereassynergy provides a 3 or 4 log reduction in viral titers. In the case ofhepatic enzymes, additivity generally provides about 25% reduction forat least one liver enzyme (alanine amino transferase or ALT, aspartateamino transferase or AST, gamma-glutamyl transpeptidase or GGTP andalpha fetoprotein or AFP) and preferably at least two, at least threeand preferably all four liver enzymes and synergy provides at leastabout 75-100% reduction in at least one liver enzymes (at least two, atthree, at least four of the liver enzymes).

The term “hepatic steatosis” or “steatohepatitis” is used to describe acondition of the liver in which inflammation is caused by a buildup offat in the liver. Hepatic steatosis is part of a group of liverdiseases, known as nonalcoholic fatty liver disease (“fatty liver” or“fatty liver disease”), in which fat builds up in the liver andsometimes causes liver damage that gets worse over time (progressiveliver damage). Non-alcoholic fatty liver disease (NAFLD) is fattyinflammation of the liver which is not due to excessive alcohol use, butis instead related to insulin resistance and metabolic syndrome, andresponds to treatments according to the present invention which affectsother insulin resistant states (e.g. diabetes mellitus type 2). Hepaticsteatosis is the most extreme form of NAFLD, and is regarded as a majorcause of cirrhosis of the liver. The present invention may be used totreat all forms of fatty liver disease, especially NAFLD, includinghepatic steatosis.

Although a cause other than viral infection is not always known, hepaticsteatosis seems also to be related to certain other conditions,including obesity, high cholesterol and triglycerides, and diabetes.Historically, treatment for hepatic steatosis involved controlling thoseunderlying diseases. Ileal brake (ileal brake hormone releasing)compositions according to the present invention, either alone or incombination with antiviral agents and/or anticancer agents may be usedto treat and/or reduce the likelihood of NASH, NAFLD and/or cirrhosis aswell as liver cancer (hepatocellular carcinoma), especially when thesedisease states or conditions occur secondary to viral infection,especially a Hepatitis B or C viral infection.

Hepatic steatosis most commonly affects people who are middle-aged andare overweight or obese, have high cholesterol and triglycerides, orhave diabetes. Despite these indications, hepatic steatosis can occur inpeople who have none of these risk factors. Excess body fat along withhigh cholesterol and high blood pressure are also signs of a conditioncalled metabolic syndrome. This condition is closely linked to insulinresistance.

Along with excess fat in the liver, which many people have, severalother factors, principally including viral infection, may contribute tothe liver damage and place individuals at risk. These are:

-   -   Resistance to insulin, which means that the body can't use sugar        (glucose) in the way it should. Normally, the body makes insulin        after a meal is eaten that has sugar in it. Insulin helps the        extra sugar in the blood get into muscles and liver. If the body        does not respond to insulin in this way, then the sugar level in        the blood will stay high. This is how insulin resistance can        increase the chance of an individual developing type 2 diabetes.    -   Changes in how the liver makes fat and what the liver does with        fat that is delivered to it by the intestines.

Other factors that have been known to contribute to hepatic steatosisinclude:

-   -   Surgeries that shorten the intestines, the stomach, or both,        such as jejunal bypass operation or biliopancreatic diversion.    -   Use of a feeding tube or other method of receiving nutrition for        a long time.    -   Use of certain medicines, including amiodarone, glucocorticoids,        synthetic estrogens, and tamoxifen.

Hepatic steatosis usually gets worse over time (deemed “progressive”),especially where the patient is infected with a virus such as HepatitisC or B. For this reason, a patient may have no symptoms until thedisease progresses to the point that it begins to affect the way theliver works (liver function). As liver damage gets worse, symptoms suchas tiredness, weight loss, and weakness may develop. It may take manyyears for hepatic steatosis to become severe enough to cause symptoms.In some limited cases, where viral infection is not implicated, theprogress of the condition can stop and even reverse on its own withouttreatment. But in other cases, especially where viral infection isimplicated, hepatic steatosis can slowly get worse and cause scarring(fibrosis) of the liver, which leads to cirrhosis and, in certain cases,hepatocellular carcinoma. In cirrhosis, the liver cells have beenreplaced by scar tissue. As more of the liver becomes scar tissue, theliver hardens and ceases to function normally.

The term “cirrhosis of the liver” or “cirrhosis” is used to describe achronic liver disease characterized by replacement of liver tissue byfibrous scar tissue as well as regenerative nodules (lumps that occur asa result of a process in which damaged tissue is regenerated), leadingto progressive loss of liver function. Cirrhosis is most commonly causedby fatty liver disease, especially including hepatic steatosis, as wellas alcoholism and especially hepatitis B and C virus causing a low gradeinflammation, which also causes hepatic steatosis, but has many otherpossible causes. Some cases are idiopathic, i.e., of unknown cause.Ascites (fluid retention in the abdominal cavity) is the most commoncomplication of end stages of cirrhosis and is associated with a poorquality of life, increased risk of infection, and a poor long-termoutcome. Other potentially life-threatening complications are hepaticencephalopathy (confusion and coma) and bleeding from esophagealvarices. Prior to the present invention, hepatic steatosis andincreasing hepatic cirrhosis was thought to be generally irreversibleonce it occurs, and historical treatment focused on preventingprogression and complications. In advanced stages of cirrhosis, the onlyoption is a liver transplant. The present invention may be used tolimit, inhibit or reduce the likelihood or treat cirrhosis of the liverwithout regard to its etiology, although cirrhosis which is secondary toa viral hepatitis infection (especially including Hepatitis C and/or B)is a particular target of the present invention.

The term “treat”, “treating”, or “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment,inhibition or reduction in the likelihood (prevention) of metabolicsyndromes, including Type 2 diabetes, hyperlipidemia, weight gain,obesity, insulin resistance, hypertension, atherosclerosis, fatty liverdiseases and certain chronic inflammatory states that lead to thesemanifestations, among others. In additional aspects, the presentinvention relates to the treatment, inhibition or reduction in thelikelihood (prevention) of hepatitis viral infections, includingHepatitis B and Hepatitis C viral infections, as well as the secondarydisease states and/or conditions which are often associated with suchviral infections, including hepatic steatosis (steatohepatitis),cirrhosis, fatty liver and hepatocellular cancer. Treatments withcombination agents or combination therapy (e.g., ileal brake hormonereleasing compound and antiviral agent and/or anticancer agents orantiviral agents and/or anticancer agents combined with Roux-en-Ygastric bypass surgery (RYGB)) represent preferred embodiments of thepresent invention.

The terms “ileal brake composition” and “ileal brake hormone releasingcomposition” are used in context to describe a compound or compositionwhich comprises an “ileum hormone-stimulating amount of a nutritionalsubstance” (also described as an “ileal brake hormone releasingsubstance” or “ileal brake compound” which includes any amount of anutritional substance that is effective to induce measurable hormonerelease in the ileum, and induce feedback from the ileum orileum-related stimulation of insulin secretion or inhibition of glucagonsecretion, or other effect such as shutting down or decreasing insulinresistance and increasing glucose tolerance. The ileal brake compositionused in the present invention may vary widely in dosage depending uponfactors such as the specific nutrient at issue, the desired effect ofadministration, the desired goal of minimizing caloric intake, and thecharacteristics of the subject to whom the ileal brake hormone releasingsubstance is administered. Preferred ileal brake compounds/ileal brakehormone releasing substances which are included in ileal brakecompositions according to the present invention include sugars, freefatty acids, lipids, polypeptides, amino acids, and compositions thatyield sugars, free fatty acids, polypeptides, or amino acids upondigestion and mixtures thereof. In preferred aspects of the presentinvention the ileal brake compound/ileal brake hormone releasingsubstance is glucose, fructose, high fructose corn syrup and mixturesthereof and optionally, a GRAS lipid or triglyceride, selected from thegroup consisting of oil from nuts (various, such as peanut, cashew,walnut, pecan, brazil nuts, etc.), coconut, palm oil, corn oil, germ,olive oil, castor, sesame, fish oil (omega 3, oleic acid and derivedliver oils) and mixtures thereof where the total amount of said ilealbrake hormone releasing substance ranges from about 500 mg to about 12.5grams, about 500 mg to about 7.5 grams, about 1 gram to about 5 gramsabout 500 mg to about 6 grams, 500 mg to about 3 grams, about 500 mg toabout 2 grams. For example, in preferred aspects of the invention, atleast about 500 mg of D-glucose is used, and a particularly preferredileum hormonal-stimulating amount of D-glucose as the ileal brakecompound includes between about 7.5-8 g to about 12-12.5 g (preferablyaround 10 g).

An ileal brake hormone releasing substance composition thus contains aneffective amount of glucose or a related sugar (including but notlimited to dextrose, sucrose, fructose) alone or in combination withoils (including but not limited to vegetable oils such as cottonseed,oils from most varieties of nuts, coconut, palm, corn, germ, olive,castor, sesame, fish oils including omega 3, oleic acid and derivedliver oils). In the practice of the invention, oils, when included, areto be emulsified, allowed to become solids in emulsified form, and thencoated for release in the ileum. When the ileal brake composition(Brake™) is produced to include both glucose and oil components asdisclosed herein, the proportion of each of these components may varyfrom 10% by weight to 90% by weight. Indeed, it is envisioned by theinventors to produce a predominant glucose formulation, a predominantoil formulation and a 50:50 mixture of glucoses and oils and remainentirely within the spirit of the invention, since optimal formulationsand combinations thereof can be defined by the direct impact onbiomarkers of the ileal brake and biomarkers of hepatic steatosis.

In addition to the ileum hormone-stimulating amount of a nutritionalsubstance (ileal brake compound) which is included in the ileal brakecomposition according to the present invention, the composition may alsoinclude “dietary components”, which in addition to glucose, lipids andother components which are included herein (e.g., such as amicro-encapsulation of glucose, lipids and other nutritional componentsas described above) includes any natural substance which either itselfevidences impact on the ileal brake, or alternatively, enhances theimpact that glucose and/or lipids have on the ileal brake, suchcomponents including other complex carbohydrates and nutritionalcomponents as otherwise described herein including, for example, alfalfaleaf, chloretlla algae, chlorophyllin and barley juice concentrate,among a number of other agents, including probiotic bacteria, all ofwhich are well known in the art.

Compositions for use in the present invention preferably comprise themicro-encapsulation of glucose, lipids and components of diet formulatedto release these active compositions at pH values between about 6.8 andabout 7.5, which allows substantial release and targets the action ofsaid medicaments at the ileal brake in the distal intestine.Conventional formulation strategies used for pharmaceuticals nevertarget release at pH values above 6.8, thereby releasing all of saidpharmaceutical earlier in the intestine than the location of the L-cellsand the ileal brake. The encapsulated compositions disclosed are apreferred medicament to reduce dietary glucose associated chronicinflammation, the primary driver of metabolic syndrome and eventualdevelopment of obesity and type 2 diabetes. Use of the encapsulatedcompositions according to the present invention decreases appetite forglucose, which is beneficial to the patient with metabolic syndrome, andthereby lowers both insulin resistance and inflammation and is ofbenefit to the treatment of patients with metabolic syndrome and relateddisease states or conditions including Type 2 diabetes, hyperlipidemia,weight gain, obesity, insulin resistance, hypertension, atherosclerosis,fatty liver diseases and certain chronic inflammatory states that leadto these manifestations, among others. In additional aspects, the abovecompositions may be used alone or co-administered with anti-viralagents, including formulating with anti-viral agents to treat hepatitisviral infections, including Hepatitis B and Hepatitis C viralinfections, as well as the secondary disease states and/or conditionswhich are often associated with such viral infections, including hepaticsteatosis (steatohepatitis), cirrhosis, fatty liver and hepatocellularcancer, among other disease states or conditions.

Therapeutic methods according to the present invention may or may notinclude concomitant or even subsequent RYGB surgery, as control ofmetabolic syndrome and related conditions and/or disease states, as wellas treating Hepatitis B and Hepatitis C viral infections, and thesecondary disease states and/or conditions which are often associatedwith such viral infections, including hepatic steatosis(steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer,among other disease states or conditions. In preferred practice of theinvention, most treatment modalities would be possible with oral use ofthe disclosed ileal brake compositions, alone or in combination with ananti-viral gents(s), with the use of RYGB surgery reserved for casesbeyond the control of said encapsulated compositions alone.

In a preferred embodiment of the invention, oral dosing with about 2,000to about 10,000 milligrams, preferably about 3,000 to about 10,000milligrams, about 7,500 to about 10,000 milligrams of a pharmaceuticalformulation comprising microencapsulated glucoses, lipids, and/or aminoacids activates the ileal brake in a dose increasing magnitude andtreats one or more of the following components of metabolic syndrome:hyperlipidemia, weight gain, obesity, insulin resistance, hypertension,atherosclerosis, fatty liver diseases and chronic inflammatory states.In alternative embodiments, the ileal brake compositions as otherwisedescribed herein are used to treat hepatitis viral infections, includingHepatitis B and Hepatitis C viral infections, as well as the secondarydisease states and/or conditions which are often associated with suchviral infections, including hepatic steatosis (steatohepatitis),cirrhosis, fatty liver and hepatocellular cancer, among other diseasestates or conditions. I

In various embodiments according to the present invention, the disclosedformulations and compositions have been described as Aphoeline which istrademarked. The other trademarked name for the ileal brake hormonereleasing substances is Brake. Compositions of the invention may be usedalone or in combination with medicaments ordinarily used to treatspecific manifestations of metabolic syndromes such as diabetes,hyperlipidemia, atherosclerosis, hypertension, obesity, insulinresistance, or chronic inflammation and/or anti-viral compounds whichare used for the treatment of hepatitis B and/or hepatitis C infections.The benefit of combination is a broader spectrum action for treatment ofmetabolic syndrome than the single agent, and additional potency of thecombination over its components. For example, compositions and methodsof treatment of the invention may employ co-administration of a drugsuch as a biguanide antihyperglycemic agent (e.g. metformin); DPP-IVinhibitors (e.g. Vildagliptin, Sitagliptin, Dutogliptin, Linagliptin andSaxagliptin); TZDs or Thiazolidinediones (which are also known to beactive on PPAR), e.g. pioglitazone, rosiglitazone, rivoglitazone,aleglitazar and the PPAR-sparing agents MSDC-0160, MSDC-0602; alphaglucosidase inhibitor including but not limited to acarbose (includingdelayed release preparations of Acarbose, Miglitol, and Voglibose);Glucokinase Activators including but not limited to TTP399 and the like;HMG-CoA reductase inhibitors. (examples of similar agents, thought toact on the defined statin pathway or by HMG-CoA reductase inhibition,include atorvastatin, simvastatin, lovastatin, ceruvastatin, pravastatinpitavastatin); angiotensin II inhibitors (AII inhibitors) (e.g.Valsartan, Olmesartan, Candesartan, Irbesartan, Losartan, Telmisartanand the like); a phosphodiesterase type 5 inhibitor (PDE5 inhibitor)such as sildenafil (Viagra), vardenafil (Levitra) and Tadalafil(Cialis®); Anti-obesity compositions that may benefit from combinationwith Brake™ include Lorcaserin and Topiramate; Combinations that willact beneficially on gastrointestinal flora include pH encapsulatedpro-biotic organisms that release the live bacteria in the ileum at a pHof about 7.0 to 7.4, these pH encapsulated probiotic bacteria may becombined further with treatments for irritable bowel disease such aslinaclotide or even with antibiotics where the goal is to restorebacterial flora after disruption by potent antibiotic therapy.Anti-viral agents including anti-hepatitis B agents and anti-hepatitis Cagents are as otherwise described herein and include, for example,Hepsera (adefovir dipivoxil), lamivudine, entecavir, telbivudine,tenofovir, emtricitabine, clevudine, valtoricitabine, amdoxovir,pradefovir, racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109,EHT899, zadaxin (thymosin alpha-1) and mixtures thereof for hepatitis Binfections and ribavirin, pegylated interferon, boceprevir, daclatasvir,asunapavir, INX-189, FV-100, NM 283, VX-950 (telaprevir), SCH 50304,TMC435, VX-500, BX-813, SCH503034, R1626, ITMN-191 (R7227), R7128,PF-868554, TT033, CGH-759, GI 5005, MK-7009, SIRNA-034, MK-0608,A-837093, GS 9190, GS 9256, GS 9451, GS 5885, GS 6620, GS 9620, GS9669,ACH-1095, ACH-2928, GSK625433, TG4040 (MVA-HCV), A-831, F351, NS5A,NS4B, ANA598, A-689, GNI-104, IDX102, ADX184, ALS-2200, ALS-2158, BI201335, BI 207127, BIT-225, BIT-8020, GL59728, GL60667, PSI-938,PSI-7977, PSI-7851, SCY-635, TLR9 Agonist, PHX1766, SP-30 and mixturesthereof for hepatitis C infections.

The term “anti-Hepatitis C agent” or “anti-HCV agent” is used throughoutthe specification to describe an agent which may be used in thetreatment of HCV and/or secondary disease states and/or conditions ofHCV infection and includes such agents as ribavirin, pegylatedinterferon, boceprevir, daclatasvir, asunapavir, INX-189, FV-100, NM283, VX-950 (telaprevir), SCH 50304, TMC435, VX-500, BX-813, SCH503034,R1626, ITMN-191 (R7227), R7128, PF-868554, TT033, CGH-759, GI 5005,MK-7009, SIRNA-034, MK-0608, A-837093, GS 9190, GS 9256, GS 9451, GS5885, GS 6620, GS 9620, GS9669, ACH-1095, ACH-2928, GSK625433, TG4040(MVA-HCV), A-831, F351, NS5A, NS4B, ANA598, A-689, GNI-104, IDX102,ADX184, ALS-2200, ALS-2158, BI 201335, BI 207127, BIT-225, BIT-8020,GL59728, GL60667, PSI-938, PSI-7977, PSI-7851, SCY-635, TLR9 Agonist,PHX1766, SP-30 and mixtures thereof, especially including one or more ofthe above in combination with ribavirin. Anti-HCV agents which may beused in the present invention may be formulated in pharmaceuticalcompositions which include an effective amount of an ileal brakecomposition, which is formulated for release in the ileum pursuant tothe present invention and may include immediate release and/or sustainedrelease and/or controlled release compositions and/or components ofanti-HCV agents as otherwise described herein.

The term “anti-Hepatitis B agent” or “anti-HBV agent” is used throughoutthe specification to describe an agent which may be used in thetreatment of HBV and includes such agents as Hepsera (adefovirdipivoxil), lamivudine, entecavir, telbivudine, tenofovir,emtricitabine, clevudine, valtoricitabine, amdoxovir, pradefovir,racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109, EHT899, zadaxin(thymosin alpha-1) and mixtures thereof. Anti-HBV agents which may beused in the present invention may be formulated in pharmaceuticalcompositions which include an effective amount of an ileal brakecomposition, which is formulated for release in the ileum pursuant tothe present invention and may include immediate release and/or sustainedrelease and/or controlled release compositions and/or components ofanti-HBV agents as otherwise described herein.

The term “anticancer agent” or “antihepatocellular cancer agent” is usedthroughout the specification to describe an anticancer agent which maybe used to inhibit, treat or reduce the likelihood of hepatocellularcancer, of the metastasis of that cancer. Anticancer agents which mayfind use in the present invention in combination with an ileal brakehormone releasing compound and in certain instances, such compoundswhich are further combined with an anti-HCV or anti-HBV agent, includefor example, nexavar (sorafenib), sunitinib, bevacizumab, tarceva(erlotinib), tykerb (lapatinib) and mixtures thereof. In addition, otheranticancer agents may also be used in the present invention, where suchagents are found to inhibit metastasis of cancer, in particular,hepatocellular cancer.

Other aspects of the invention relate to compositions which comprise aneffective amount of an ileal brake hormone releasing substance asotherwise described herein, preferably glucose or dextrose which isformulated in delayed and/or controlled release dosage form in order torelease an effective amount of ileal brake hormone releasing substancein the ileum of the patient or subject to whom compositions according tothe present invention are administered, generally, at least about 50% ofthe total amount of the ileal brake hormone releasing substance present,and preferably at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, and at least about 95% ormore of the ileal brake hormone releasing substance present in thecomposition. In the case of D-glucose or dextrose as the ileal brakehormone releasing substance, it is preferred that at least about 2.5grams, at least about 3 grams, at least about 7.5 grams and morepreferably about 10-12.5 grams or more of glucose be released in thepatient's or subject's ileum in order to stimulate ileal hormonerelease.

Compositions according to the present invention comprise effectiveamounts of ileal brake hormone releasing substance, preferably D-glucoseor dextrose, which may be combined with at least one delayed orcontrolled release component such as a delayed/controlled releasepolymer or compound such as a cellulosic material, including, forexample, ethyl cellulose, methyl cellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone, cellulose acetatetrimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP),polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP),shellac, copolymers of methacrylic acid and ethyl acrylate, copolymersof methacrylic acid and ethyl acrylate to which a monomer ofmethylacrylate has been added during polymerization, a mixture ofamylose-butan-1-ol complex (glassy amylose) with Ethocel® aqueousdispersion, a coating formulation comprising an inner coating of glassyamylose and an outer coating of cellulose or acrylic polymer material,pectins (of various types), including calcium pectinate, carageenins,aligns, chondroitin sulfate, dextran hydrogels, guar gum, includingmodified guar gum such as borax modified guar gum, beta-cyclodextrin,saccharide containing polymers, e.g., a polymeric construct comprising asynthetic oligosaccharide-containing biopolymer including methacrylicpolymers covalently coupled to oligosaccharides such as cellobiose,lactulose, raffinose and stachyose, or saccharide-containing, naturalpolymers including modified mucopolysaccharides such as cross-linkedpectate; methacrylate-galactomannan, pH-sensitive hydrogels andresistant starches, e.g., glassy amylose. Other materials includemethylmethacrylates or copolymers of methacrylic acid andmethylmethacrylate having a pH dissolution profile that delays releasein vivo of the majority of the ileal brake hormone releasing substanceuntil the dosage form reaches the ileum may also be used. Such materialsare available as Eudragit® polymers (Rohm Pharma, Darmstadt, Germany).For example, Eudragit® L100 and Eudragit® S100 can be used, either aloneor in combination. Eudragit® L100 dissolves at pH 6 and upwards andcomprises 48.3% methacrylic acid units per g dry substance; Eudragit®S100 dissolves at pH 7 and upwards and comprises 29.2% methacrylic acidunits per g dry substance. Generally, the encapsulating polymer has apolymeric backbone and acid or other solubilizing functional groups.Polymers which have been found suitable for purposes of the presentinvention include polyacrylates, cyclic acrylate polymer, polyacrylicacids and polyacrylamides. A particularly preferred group ofencapsulating polymers are the polyacrylic acids Eudragit® L andEudragit® S which optionally may be combined with Eudragit® RL or RS.These modified acrylic acids are useful since they can be made solubleat a pH of 6 or 7.5, depending on the particular Eudragit chosen, and onthe proportion of Eudragit® S to Eudragit® L, RS, and RL used in theformulation. By combining one or both of Eudragit® L and Eudragit® Swith Eudragit® RL and RS (5-25%), it is possible to obtain a strongercapsule wall and still retain the capsule's pH-dependent solubility.

A delayed and/or controlled release oral dosage form used in theinvention can comprise a core containing an ileum hormonal-stimulatingamount of an ileal brake hormone releasing substance along withcarriers, additives and excipients that is coated by an enteric coating.In some embodiments, the coating comprises Eudragit® L100 and shellac,or food glaze Eudragit® S100 in the range of 100 parts L100:0 parts S100to 20 parts L100:80 parts S100, more preferably 70 parts L100:30 partsS100 to 80 parts L100:20 parts S100. In preferred alternatives, thepreferred coating is a nutrateric coating which dissolves at the pH ofthe ileum (about 7-8, about 7.2-8.0, about 7.4-8.0, about 7.5-8.0)comprising a shellac, and emulsifiers such as triacetone andhypromellose, among others. Alternative nutrateric coatings includeethyl cellulose, ammonium hydroxide, medium chain triglycerides, oleicacid, and stearic acid. As the pH at which the coating begins todissolve increases, the thickness necessary to achieve ileum-specificdelivery decreases. For formulations where the ratio of Eudragit®L100:S100 is high, a coat thickness of the order 150-200 m can be used.For coatings where the ratio Eudragit® L100:S100 is low, a coatthickness of the order 80-120 m can be used in the present invention.

Compositions for use in the present invention preferably comprise themicro-encapsulation of the ileal hormone releasing compounds, e.g.,glucose, lipids and dietary components as described hereinaboveformulated to release these active compositions at pH values betweenabout 6.8 and about 7.5 preferably about 7.0 to about 7.5, which allowssubstantial release and targets the action of said medicaments at theileal brake in the distal intestine. Conventional formulation strategiesused for pharmaceuticals never target release at pH values above 6.8.These compositions may be used alone or formulated in combination withan anti-viral agent (preferably an anti-HCV or anti-HBV agent) or otherbioactive agent (an anticancer agent effective for example in thetreatment of hepatocellular cancer) as otherwise described herein, wherethe antiviral and/or other bioactive agent is formulated as an immediaterelease composition and/or a sustained and/or controlled releasecomposition in combination with the ileal hormone releasing compounds.Use of the encapsulated compositions according to the present inventiondecreases appetite for glucose, which is beneficial to the patient withmetabolic syndrome, and thereby lowers both insulin resistance andinflammation and is of benefit to the treatment of patients withmetabolic syndrome and related disease states or conditions includingType 2 diabetes, hyperlipidemia, weight gain, obesity, insulinresistance, hypertension, atherosclerosis, fatty liver diseases andcertain chronic inflammatory states that lead to these manifestations,among others. In additional aspects, the above compositions may be usedalone or co-administered with anti-viral agents, including formulatingwith anti-viral agents to treat hepatitis viral infections, includingHepatitis B and Hepatitis C viral infections, as well as the secondarydisease states and/or conditions which are often associated with suchviral infections, including hepatic steatosis (steatohepatitis),cirrhosis, fatty liver and hepatocellular cancer, among other diseasestates or conditions.

Compositions according to the present invention may be administered atvarious times during the day (e.g., once a day, twice a day, four timesa day) in order to produce the intended effect, i.e., effectivetreatment of metabolic syndrome, including Type 2 diabetes,hyperlipidemia, weight gain, obesity, insulin resistance, hypertension,atherosclerosis, fatty liver diseases and certain chronic inflammatorystates that lead to these manifestations, among others, as well as totreat, inhibit or reduce the likelihood of hepatitis viral infections,including Hepatitis B and Hepatitis C viral infections, as well as thesecondary disease states and/or conditions which are often associatedwith such viral infections, including hepatic steatosis(steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer,among other disease states or conditions related to same. Preferably,compositions according to the present invention are administered oncedaily, whereby all components, i.e., the ileal hormone release compoundand any bioactive agent (including an antiviral agent and/or ananticancer agent as otherwise described herein), if included, are insustained or controlled release form. In certain aspects, the ilealhormone release compound is in sustained or controlled release form andthe bioactive agent is in both immediate and sustained or controlledrelease form.

In another embodiment, the invention provides a method of treatmentcomprising once-daily administration to the subject of a delayed and/orcontrolled release oral dosage form with the target site being the ilealbrake. In this aspect of the invention, the dosage form is administeredwhile the subject is in the fasted state and at a time of around six toaround nine hours prior to the subject's next intended meal. The dosageform comprises an enterically-coated, ileum hormone-stimulating amountof ileal brake hormone releasing substance and releases the majority ofthe ileal brake hormone releasing substance in vivo upon reaching thesubject's ileum. This formulation may be used alone or in combinationwith another bioactive agent, including an anti-viral agent such as ananti-HCV or anti-HBV agent or an anticancer agent. Additionally, thisformulation may be further combined with immediate, sustained orcontrolled release bioactive agent, including an anti-viral agent suchas an anti-HCV or anti-HBV agent or anticancer agent, or combined withboth immediate and sustained or controlled release bioactive agent inorder to influence the bioavailability of the bioactive agent combinedwith the ileal break hormone releasing substance.

In still another embodiment, the invention provides a method oftreatment by administering to the subject a delayed and/or controlledrelease oral dosage form comprising an enterically-coated, ileumhormone-stimulating amount of an ileal brake hormone releasingsubstance. The dosage form is administered while the subject is in thefasted state and at a time of around four and one-half to ten hours,more preferably around six to around nine hours prior to the subject'snext intended meal. The dosage form comprises an enterically-coated,ileum hormone-stimulating amount of ileal brake hormone releasingsubstance and releases the majority of the ileal brake hormone releasingsubstance in vivo upon reaching the subject's ileum. This formulationmay be used alone or in combination with another bioactive agent,including an anti-viral agent such as an anti-HCV or anti-HBV agent.Additionally, this formulation may be further combined with immediate,sustained or controlled release bioactive agent, including an anti-viralagent such as an anti-HCV or anti-HBV agent, or combined with bothimmediate and sustained or controlled release bioactive agent in orderto influence the bioavailability of the bioactive agent combined withthe ileal break hormone releasing substance.

In still other preferred embodiments, the invention provides methods forcontrol of metabolic syndrome and its various detrimental actions,through specific biochemical pathways that stabilize blood glucose andinsulin levels, and treating gastrointestinal and hepatic inflammatorydisorders comprising once-daily administration to a subject in needthereof of a delayed and/or controlled release composition which maycomprise an emulsion or a microemulsion containing an ileumhormone-stimulating amount of ileal brake hormone releasing substance.The composition is administered while the subject is in the fasted stateand at a time of around four to ten, preferably around six to aroundnine hours prior to the subject's next intended meal. The compositionreleases the majority of the ileal brake hormone releasing substance invivo upon reaching the subject's ileum, the site of its intended effect.Other bioactive agents are released pursuant to the formulationprovided, whether immediate release, sustained or controlled release orimmediate and sustained or controlled release.

In preferred embodiments of the aforementioned methods of treatment ofthe invention, the dosage form is administered once-daily at bedtime, orin AM.

By administering the dosage form to a subject in the fasted state ataround four to ten, around six to around nine hours prior to thesubject's next intended meal, and delivering substantially all of theileal brake hormone releasing substance to the ileum, methods andcompositions of the invention achieve improved levels of plasmagastrointestinal hormones and prove useful in the treatment orprevention of one or more of metabolic syndrome and/or type II diabetesmellitus, as well as hyperlipidemia, weight gain, obesity, insulinresistance, hypertension, atherosclerosis, fatty liver diseases andcertain chronic inflammatory states that lead to these manifestations,among others, as well as hepatitis viral infections, including HepatitisB and Hepatitis C viral infections, as well as the secondary diseasestates and/or conditions which are often associated with such viralinfections, including hepatic steatosis (steatohepatitis), cirrhosis,fatty liver and hepatocellular cancer, among other disease states orconditions The benefit of obtaining at least twenty-four hour appetitesuppression and improved blood glucose and insulin levels from a singleoral dosage of an inexpensive ileal brake hormone releasing substancealone or in combination with a bioactive agent as otherwise describedherein increases the likelihood that the subject will adhere to themethods of treatment for an extended time (improved patient compliance),thereby achieving a maximum health benefit. Further, compositions andmethods of the invention utilize ileal brake hormone releasingsubstances that are free of the safety and cost concerns associated withpharmacological and surgical intervention, and can induce long-termcontrol of appetite, inflammation, insulin resistance andhyperlipidemia.

In another embodiment, the invention provides a delayed and/orcontrolled release oral dosage form comprising an effective amount of anileal brake hormone releasing substance, preferably D-glucose ordextrose in an amount effective when released in the ileum to stimulateor inhibit the release of hormones in that portion of the smallintestine of a subject or patient. This dosage form is administered inaccordance with, and achieves the advantages of, the aforementionedmethods of treatment of the invention. In addition, the presentinvention provides a method for diagnosing metabolic syndrome (glucoseintolerance) and/or type II diabetes in a patient or subject.

Thus, the invention provides methods of stimulating or inhibiting thehormones (depending on the hormone) of the ileum in an easy andreproducible or standardized way (orally) which did not exist prior tothe present method. Indeed, RYGB surgery is the only other way torelease these ileal brake hormones and invoke mimicry of the effects ofthe present invention. Pursuant to the present application, the testingon a large scale of the ileal release to study and classify thevariation or pathology of the hormone releases as such release relatesto control of metabolic syndromes or type 2 diabetes and relatedpathological states and conditions, and the effect these hormones haveon the rest of the metabolic and hormonal status of the body is anotheraspect of the invention. Thus, the present method allows theintroduction of one or more dosages in oral dosage form to the ileum ofthe patient which can be standardized sufficiently to allow the creationof a normal reference range for the hormonal stimulation. It has beendiscovered that the present invention can be used to probe differentdiseases stemming from the relative or absolute increase or decrease ofthe ileal hormones, not only in treating the overweight/obesitymetabolic syndrome axis but a number of other gastrointestinal diseasesas otherwise described herein.

In particular aspects, the present invention is directed to treating,inhibiting or reducing the likelihood of hepatitis infections,especially including hepatitis C or B viral infections and secondarydisease states and conditions which may occur as a consequence of suchinfection, which may include metabolic syndrome, Type 2 diabetes,hyperlipidemia, weight gain, obesity, insulin resistance, hypertension,atherosclerosis, fatty liver diseases and certain chronic inflammatorystates that lead to these manifestations, and especially such secondarydisease states and conditions including hepatic steatosis(steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer,among other disease states or conditions

Particular and Preferred Methods of the Present Invention Include theFollowing:

Hepatic Steatosis, fatty liver disease, NASH and NAFLD may beeffectively treated by an orally administered, ileal brake hormonereleasing substance according to the present invention which lowerselevated insulin resistance, and lowers elevated liver enzymes such asALT and AST, and lowers serum triglycerides by mimicry of the effect ofsurgery, preferably Roux-en-Y gastric bypass surgery (RYGB).

The hepatic steatosis treatment as described above, may be preferablycombined with an anti-viral drug active against Hepatitis C and/orHepatitis B, to lower elevated virus counts and concomitantly improvethe health of the steatotic cells in liver of the patient with hepatitisC.

In the hepatic steatosis treatment described above, the primarybeneficial action of the ileal brake hormone releasing substance (ilealbrake compound) is to decrease the supply of glucose to the liver andtriglyceride synthesis that the virus also uses as part of this pathwayto reproduce, and thereby lower the degree of fatty accumulation in theliver, and limit viral reproduction and further injury to the liver.

The synergistic combination of the specific antiviral treatment andileal brake hormone releasing substance combination used for treatmentof hepatitis C (and in certain instances, hepatitis B); where theprimary beneficial action of the antiviral is to decrease the viralinjury to steatotic hepatic cells and the primary beneficial action ofthe ileal brake hormone releasing substance (ileal brake compound) is todecrease the supply of glucose and triglycerides synthesis in the liver,and thereby lower the number of hepatic cells that become steatotic andat risk for extension of the viral infection and further hepatic injury.The favorable effect on other secondary conditions such as cirrhosis,fatty liver and hepatocellular cancer is also significant and in mostinstances, synergistic.

The present invention is also directed to the synergistic combinationtreatment for hepatitis C by administering an ileal brake compound asdescribed above in combination with an anti-hepatitis C viral agentwherein the antiviral medicament is pegylated interferon and/orribavirin in a therapeutically useful dosage and duration. Thistreatment can be used alone or combined with an effective amount of atleast one additional anti-HCV agent as otherwise described herein. Theseagents include, for example, boceprevir, daclatasvir, asunapavir,INX-189, FV-100, NM 283, VX-950 (telaprevir), SCH 50304, TMC435, VX-500,BX-813, SCH503034, R1626, ITMN-191 (R7227), R7128, PF-868554, TT033,CGH-759, GI 5005, MK-7009, SIRNA-034, MK-0608, A-837093, GS 9190, GS9256, GS 9451, GS 5885, GS 6620, GS 9620, GS9669, ACH-1095, ACH-2928,GSK625433, TG4040 (MVA-HCV), A-831, F351, NS5A, NS4B, ANA598, A-689,GNI-104, IDX102, ADX184, ALS-2200, ALS-2158, BI 201335, BI 207127,BIT-225, BIT-8020, GL59728, GL60667, PSI-938, PSI-7977, PSI-7851,SCY-635, TLR9 Agonist, PHX1766, SP-30 and mixtures thereof. These agentsmay be used alone, in combination, or further in combination witheffective amounts of ribavirin, pegylated interferon or mixturesthereof.

For example, in a particular aspect, the present invention is directedto the synergistic co-administration of an ileal brakecompound/composition with an effective antiviral combination ofpegylated interferon and/or ribavirin in a therapeutically useful dosageand duration, combined with boceprevir in a dosage of at least 800 mgthree times daily.

In a further aspect, the present invention is directed to thesynergistic co-administration of an ileal brake compound/compositionwith an effective antiviral combination of pegylated interferon and/orribavirin in a therapeutically useful dosage and duration, combined withtelaprevir in a dosage of at least 750 mg three times daily.

In a further aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral combination of the NS5A replication complexinhibitor daclatasvir in an effective dose combined with the NS3protease inhibitor asunaprevir in an effective dose and either or bothof these protease inhibitors can be used alone or in combination withpegylated interferon and/or ribavirin in an effective amount.

In still an additional aspect, the present invention relates to asynergistic co-administration of an ileal brake compound/compositionwith an effective antiviral in combination wherein the antiviralmedicament is daclatasvir, an NS5A replication complex inhibitor used inan effective amount alone or in combination with pegylated interferonand/or ribavirin in an effective amount.

In still another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isasunaprevir a NS3 protease inhibitor used in an effective amount aloneor in combination with pegylated interferon and/or ribavirin in aneffective amount.

In yet an additional aspect, the present invention relates to asynergistic co-administration of an ileal brake compound/compositionwith an effective antiviral in combination, wherein the antiviralmedicament is INX-189, a nucleotide polymerase inhibitor used in aneffective amount, alone or in combination with pegylated interferonand/or ribavirin in an effective amount.

In still another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isFV-100, a bicyclic nucleoside analogue, used in an effective amount,alone or in combination with pegylated interferon and/or ribavirin in aneffective amount.

In still another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isGS 9190, a non-nucleoside polymerase inhibitor, used in an effectiveamount, alone or in combination with pegylated interferon and/orribavirin in an effective amount.

In still another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isGS 9256, a NS3 protease inhibitor, used in an effective amount, alone orin combination with pegylated interferon and/or ribavirin in aneffective amount.

An additional aspect of the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isGS 9451, a NS3 protease inhibitor, used in an effective amount, alone orin combination with pegylated interferon and/or ribavirin in aneffective amount.

In still a further aspect, the present invention relates to asynergistic co-administration of an ileal brake compound/compositionwith an effective antiviral in combination, wherein the antiviralmedicament is GS 5885, a NS5A inhibitor, used in an effective amount,alone or in combination with pegylated interferon and/or ribavirin in aneffective amount.

In another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isGS 6620, a nucleotide polymerase inhibitor, used in an effective amount,alone or in combination with pegylated interferon and/or ribavirin in aneffective amount.

Still another aspect or the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isGS 9620, a TLR-7 agonist, used in an effective amount, alone or incombination with pegylated interferon and/or ribavirin in an effectiveamount.

In another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isGS 9669, a non-nucleoside polymerase inhibitor, used in an effectiveamount, alone or in combination with pegylated interferon and/orribavirin in an effective amount.

In a further aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isPSI-938, a guanine nucleotide analog polymerase inhibitor, used in aneffective amount, alone or in combination with pegylated interferonand/or ribavirin in an effective amount.

In yet another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isPSI-7977, a nucleotide analog, used in an effective amount, alone or incombination with pegylated interferon and/or ribavirin in an effectiveamount.

In yet a further aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isSCY-635, a non-immunosuppressive cyclophilin inhibitor, used in aneffective amount, alone or in combination with pegylated interferonand/or ribavirin in an effective amount.

In another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isBI 201335, an inhibitor of NS3/4A protease, used in an effective amount,alone or in combination with pegylated interferon and/or ribavirin in aneffective amount.

In yet another additional aspect, the present invention relates to asynergistic co-administration of an ileal brake compound/compositionwith an effective antiviral in combination, wherein the antiviralmedicament is BI 207127, an inhibitor of the NS5B non-nucleosidepolymerase, used in an effective amount, alone or in combination withpegylated interferon and/or ribavirin in an effective amount.

In an additional aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isACH-2928, an inhibitor of the NS5A non-nucleoside polymerase, used in aneffective amount, alone or in combination with pegylated interferonand/or ribavirin in an effective amount.

In another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isINX-189, a protide which is a phosporamidate nucleotide analog used inan effective amount, alone or in combination with pegylated interferonand/or ribavirin in an effective amount.

In another aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isALS-2200, an inhibitor of the NS5B non-nucleoside polymerase used in aneffective amount alone or with pegylated interferon and/or ribavirin inan effective amount.

In an additional aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isALS-2158, an inhibitor of the NS5B non-nucleoside polymerase used in aneffective amount alone or with pegylated interferon and/or ribavirin inan effective amount.

In yet a further aspect, the present invention relates to a synergisticco-administration of an ileal brake compound/composition with aneffective antiviral in combination, wherein the antiviral medicament isBIT-225, an inhibitor of the targeted p& protein used in an effectiveamount, alone or with pegylated interferon and/or ribavirin in aneffective amount.

In another further aspect, the present invention relates to asynergistic co-administration of an ileal brake compound/compositionwith an effective antiviral in combination, wherein the antiviralmedicament is BL-8020, an inhibitor of Hepatitis C virus (HCV)-inducedautophagy used in an effective amount alone or with pegylated interferonand/or ribavirin in an effective amount.

Predictive Methods for Response in Hepatitis C Patients

Predicting clinical outcomes in patients with chronic hepatitis C isconsidered challenging. Ghany and colleagues (9) used the Hepatitis CLong-Term treatment against Cirrhosis (HALT-C) trial database to developtwo prediction models, using baseline values of routinely availablelaboratory tests together with changes in these values during follow-upto predict clinical decompensation and liver-related death/livertransplant in patients with advanced hepatitis C. Patients randomized tono treatment and who had >/=2-year follow-up without a clinical outcomewere included in the analysis. Four variables (platelet count, aspartateaminotransferase [AST]/alanine aminotransferase [ALT] ratio, totalbilirubin, and albumin) with three categories of change (stable, mild,or severe) over 2 years were analyzed. Cumulative incidence of clinicaloutcome was determined by Kaplan-Meier analysis and Cox regression wasused to evaluate predictors of clinical outcome. In all, 470 patientswith 60 events were used to develop models to predict clinicaldecompensation. Baseline values of all four variables were predictive ofdecompensation. There was a general trend of increasing outcomes withmore marked worsening of laboratory values over 2 years, particularlyfor patients with abnormal baseline laboratory test values. A model thatincluded baseline platelet count, AST/ALT ratio, bilirubin, and severeworsening of platelet count, bilirubin, and albumin was the bestpredictor of clinical decompensation. A total of 483 patients with 79events were used to evaluate predictors of liver-related death or livertransplant. A model that included baseline platelet count and albumin aswell as severe worsening of AST/ALT ratio and albumin was the bestpredictor of liver-related outcomes. These authors concluded that boththe baseline value and the rapidity in change of the value of routinelaboratory variables were shown to be important in predicting clinicaloutcomes in patients with advanced chronic hepatitis C (9).

Another means of predicting response of Hepatitis C to pegIFN/Riba isthe viral response linked change in insulin resistance, a parameter ofinterest to us because it is one of the earliest effects of both RYGBand Brake™ In their study, Thompson and colleagues (10) examinedgenotype-specific associations between hepatitis C virus and insulinresistance. Specifically, this study investigated the associationbetween a sustained virological response (SVR) and insulin resistanceafter chronic treatment with interferon/ribavirin therapy. They enrolled2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 fromtwo phase 3 trials where patients were treated for either 24 or 48weeks. Insulin resistance was measured before treatment and 12 weeksafter treatment using homeostasis model assessment (HOMA)-IR. PairedHOMA-IR measurements were available in 1038 non-diabetic patients (497with genotype 1; 541 with genotype 2/3). At baseline the prevalence ofHOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs.27%; p=0.048). There was a significant reduction in the prevalence of IRin patients with genotype 1 achieving SVR (delta 10%; p<0.001), but notin genotype 1 nonresponders or those with genotype 2/3. Multivariateanalysis indicated that SVR was associated with a significant reductionin mean HOMA-IR in patients with genotype 1 (p=0.004), but not in thosewith genotype 2/3, which was independent of body mass index, ALT, GGTPand lipid level changes. It was thought that genotype 1 may have adirect effect on the development of insulin resistance, independent ofhost metabolic factors, and may be partially reversed by viraleradication (10). This study partially justifies the study of parameterslinked to hepatic steatosis, but this variable was not directly measuredin this trial.

Several studies of T2D and metabolic syndrome patients with and withoutHepatitis C provide further support for Hepatic steatosis, common indiabetes, (11, 12) as the usual cause of elevated liver enzymes, andlink the insulin resistance, glucose intolerance and elevatedtriglycerides to the development of hepatic steatosis. Stated simply,the steatosis is present because of the metabolic syndrome even withoutovert T2D. Once present, the hepatic steatosis interacts with thehepatitis C virus to make eradication more difficult. Finally, the liverenzymes only decline in hepatitis C treatments where the metabolicsyndrome is also resolved, such as in the study of Thompson (10). Dixonand colleagues (13) directly studied the effect of gastric bandingassociated weight loss on nonalcoholic fatty liver disease in a caseseries of 36 selected obese patients. These 36 patients (11 males, 25females) had paired liver biopsies, the first at the time oflaparoscopic adjustable gastric band placement and the second afterweight loss. Second biopsies were obtained from two groups: thoserequiring a subsequent laparoscopic procedure (n=19) and those withindex biopsy score of 2 or greater for zone 3-centric hepatic fibrosis(n=17). All biopsies were scored, blinded to the patient's identity andclinical condition, for individual histological features and for NASHstage and grade. Initial biopsies demonstrated NASH in 23 patients andsteatosis in 12 patients. Repeat biopsies were taken at 25.6+/−10 months(range, 9-51 months) after band placement. Mean weight loss was34.0+/−17 kg, and percentage of excess weight loss was 52+/−17%. Therewere major improvements in lobular steatosis, nacre-inflammatorychanges, and fibrosis at the second biopsy (P<0.001 for all). Portalabnormalities remained unchanged. Only four of the repeat biopsiesfulfilled the criteria for NASH, implying that this procedure wasessentially a cure. There were 18 patients with an initial fibrosisscore of 2 or more compared with 3 patients at follow-up (P<0.001). Thepatients with the metabolic syndrome in this series (n=23) who had moreextensive changes before surgery, had greater improvement with resultingweight loss. Dixon and colleagues concluded that weight loss afterbariatric surgery provides major improvement or resolution of obesityand metabolic syndrome-associated abnormal liver histological featuresin severely obese subjects (13).

Hickman and colleagues noted that raised liver enzymes are common intype 2 diabetes (T2DM) but often considered benign. Non-alcoholic fattyliver, including hepatic steatosis was the cause in 65% of cases butother causes included alcoholic liver disease and viral hepatitis.Cirrhosis was identified in 11 patients. These investigators noted asignificant burden of advanced liver diseases from a variety ofetiologies in patients with T2DM. (14).

Forlani conducted an observational point prevalence study on hepaticdisease and raised liver enzymes in Type 2 diabetes in eighthospital-based Italian diabetes units. Data of 9621 consecutive Type 2diabetes patients (males, 52.4%; median age, 65 yr) were analyzed, andalanine and aspartate aminotransferase (ALT, AST) and gamma-glutamyltransferase (GGPT) levels were related to body mass index (BMI),metabolic control and the presence of the metabolic syndrome. They notedALT, AST, and GGPT levels exceeding the upper limit of normal werepresent in 16.0%, 8.8%, and 23.1%, respectively, the prevalence beinghigher in males, increasing with obesity class and poor metaboliccontrol, and decreasing with age. Elevated enzymes were systematicallyassociated with most parameters of the metabolic syndrome. Aftercorrection for age, gender, BMI, and differences across centers,elevated triglyceride levels/fibrate treatment [odds ratio (OR), 1.57;95% confidence interval (CI), 1.34-1.84] and an enlarged waistcircumference (OR, 1.47; 95% CI, 1.17-1.85) were the only parametersindependently associated with high ALT. In a separate analysis, thepresence of metabolic syndrome (Adult Treatment Panel III criteria) washighly predictive of raised liver enzymes. After exclusion of hepatitisB and C positive cases, tested in 2 centers, the prevalence of raisedenzymes decreased by approximately 4%, but the association with themetabolic syndrome did not change significantly. In conclusion, the highprevalence of elevated liver enzymes in Type 2 diabetes is in keepingwith the well-demonstrated risk of progressive liver disease (15).

Probiotics are closely associated with metabolic syndrome and hepaticsteatosis. A study by Kirpich and colleagues examined the potentialtherapeutic role of probiotics in alcohol-induced liver injury in 66adult Russian males admitted to a psychiatric hospital with a diagnosisof alcoholic psychosis. Patients were randomized to receive 5 days ofBifidobacterium bifidum and Lactobacillus plantarum 8PA3 versus standardtherapy alone (abstinence plus vitamins). Stool cultures and liverenzymes were performed at baseline and again after therapy. Results werecompared between groups and with 24 healthy, matched controls who didnot consume alcohol. Compared to healthy controls, alcoholic patientshad significantly reduced numbers of bifidobacteria (6.3 vs. 7.5 logcolony-forming unit [CFU]/g), lactobacilli (3.15 vs. 4.59 log CFU/g),and enterococci (4.43 vs. 5.5 log CFU/g). The mean baseline ALT, AST,and GGTP activities were significantly elevated in the alcoholic groupcompared to the healthy control group (AST: 104.1 vs. 29.15 U/L; ALT:50.49 vs. 22.96 U/L; GGT 161.5 vs. 51.88 U/L), indicating that thesepatients did have mild alcohol-induced liver injury. After 5 days ofprobiotic therapy, alcoholic patients had significantly increasednumbers of both bifidobacteria (7.9 vs. 6.81 log CFU/g) and lactobacilli(4.2 vs. 3.2 log CFU/g) compared to the standard therapy arm. Despitesimilar values at study initiation, patients treated with probiotics hadsignificantly lower AST and ALT activity at the end of treatment thanthose treated with standard therapy alone (AST: 54.67 vs. 76.43 U/L; ALT36.69 vs. 51.26 U/L). In a subgroup of 26 subjects withwell-characterized mild alcoholic hepatitis (defined as AST and ALTgreater than 30 U/L with AST-to-ALT ratio greater than one), probiotictherapy was associated with a significant end of treatment reduction inALT, AST, GGT, lactate dehydrogenase, and total bilirubin. In thissubgroup, there was a significant end of treatment mean ALT reduction inthe probiotic arm versus the standard therapy arm. In conclusion,patients with alcohol-induced liver injury have altered bowel floracompared to healthy controls. Short-term oral supplementation with B.bifidum and L. plantarum 8PA3 was associated with restoration of thebowel flora and greater improvement in alcohol-induced liver injury thanstandard therapy alone (16). This study points to additional methods forcontrol of hepatic inflammation and liver enzyme elevation.

Progressive liver disease in hepatitis C is also monitored withbiomarkers of hepatic fibrosis. Fontana and colleagues examined serumfibrosis marker levels during the lead-in treatment phase of patientsenrolled in the Hepatitis C Antiviral Long-term Treatment againstCirrhosis (HALT-C) trial. After the trial, the week 0, 24, 48, and 72serum samples were analyzed for YKL-40, tissue inhibitor of matrixmetalloproteinase-1, amino-terminal peptide of type III procollagen(PIIINP), and hyaluronic acid (HA) levels. All 456 chronic hepatitis Cpatients received pegIFN/Riba for 24 to 48 weeks. Mean age of thepatients was 49.2 years, 71% were male, and 39% had cirrhosis atbaseline. Lower pretreatment serum YKL-40, tissue inhibitor of matrixmetalloproteinase-1, PIIINP, and HA levels were associated significantlywith a week-20 early virologic response (P<0.0001). In multivariateanalysis, non-1 genotype, non-black race, prior interferon monotherapy,and lower baseline serum ALT/AST levels and log(10)YKL-40 levels wereassociated independently with week-20 virologic response. Statisticallysignificant declines in all marker levels were observed at week 72compared with baseline in the 81 patients with a sustained virologicresponse, but not in the 72 patients with breakthrough or relapse. Atweeks 24 and 48, significant increases were observed in serum PIIINP andHA levels in nonresponders compared with virologic responders(P<0.0001). Fontana and colleagues concluded that elevated pretreatmentYKL-40 levels are an independent predictor of initial virologic responseto pegIFN/Riba treatment. Levels of all 4 serum fibrosis markersdecreased significantly in the SVR patients, consistent with reducedhepatic fibrogenesis. Measuring serum fibrosis marker levels before andafter antiviral therapy may provide important indicators of response inpatients with hepatitis C (17).

New agents are here for treatment of hepatitis C, for exampleboceprevir, an NS3 protease inhibitor, which is approved for use incombination with pegIFN/Riba. PegIFN/Riba alone achieves sustainedvirological response (SVR) in fewer than half of patients with genotype1 chronic hepatitis C virus infection treated for 48 weeks. Kwo andcolleagues tested the efficacy of boceprevir, an NS3 hepatitis C virusoral protease inhibitor, when added to pegIFN/Riba for genotype 1hepatitis C virus. The primary endpoint was SVR 24 weeks aftertreatment. In patients with untreated genotype 1 chronic hepatitis Cinfection, the addition of the direct-acting antiviral agent boceprevirto standard treatment with pegIFN/Riba doubles the sustained responserate compared with that recorded with standard treatment alone (18).There are similar studies with telaprevir. Although over 60% of thestudy patients have hepatic steatosis at baseline, data on any endpointof response other than viral load is completely absent in these studies,and there are no biomarkers of metabolic syndrome measured or assessed.

Thus, it does not appear that the newer drugs such as boceprevir ortelaprevir change liver enzymes or any marker of hepatic steatosis inpatients, even though these two newer protease inhibitor drugs are usedin combination with pegIFN/Riba (2, 19-24)

Regarding the role of antiviral agents in the control of hepaticsteatosis, it would be unexpected to see change in liver enzymes orresolution of hepatic inflammation with the use of any of the antiviraldrugs available, particularly if the regimen does not includepegIFN/Riba. Clearly, none of these drugs directly manages the hepaticsteatosis, which is a highly significant predictor of treatment failureor relapse (25). Thus the discovery that management of hepatic steatosiswith either RYGB or orally administered Brake™ offers promise of anothermajor advance in the treatment of hepatitis C infection.

By way of example and illustration of the role of an ileal brakecompound or composition (Brake™) in hepatitis C treatment, the inventorsdescribe here some patient cases to demonstrate unexpected favorableoutcomes in difficult treatment cases with hepatitis C where theresponse was better than expected when the patient was given Brake™

Aphoeline Formulation 1

600 mg/capsule glucose

1000 mg capsule

10% Eudragit coating

Plasticizer (propylene glycol, triethyl acetate and water)

Magnesium stearate

Silicon Dioxide

Formulation II Amount Range Blend: Alfalfa Leaf 3.00 1-10+ ChlorellaAlgae 3.00 1-10+ Chlorophyllin 3.00 1-10+ Barley Grass Juice Concentrate3.00 1-10+ Dextrose 1429.00 500-3000+ Other Tablet Ingredients:Coating * 388.40 125-750+  Corn Starch NF 80.00 25-160+ Hypromellose USP32.40 10-65+  Stearic Acid NF (Vegetable Grade) 19.50 6.5-35+  TriacetinFCC/USP 19.30 6.5-40+  Magnesium Stearate NF/FCC 7.00 2.5-15+  SiliconDioxide FCC 2.50 0.75-5.0+  * Depending upon the composition used, 10%by weight Aqueous Shellac (Mantrose Haeuser, Inc. Aphoeline-1), 8% byweight Aqueous Indian Shellac (Aphoeline-2) was used to coat theformulations.

Formulation II was provided by mixing the actives with corn starch,stearic acid, magnesium stearate and silicon dioxide and pressing into atablet, and coating the tablet with shellac (either 10% or 8% shellac),triacetin and the hypromellose. A Eudragit coating could alternativelybe used, similar to that which coats formulation I, as described above.

Example 1. Comparison of the Impact of Brake™ in 18 Patients vs. RYGB in15 Patients from the Perspective of Insulin Resistance, on HepaticEnzymes and Triglycerides

A. Brake™ Treatment Population

Briefly, Aphoeline Brake™ formulation 2 (described above) was given fora minimum of 6 months to a group of 18 patients. Demographics of the 18patients were as follows.

9 males, 9 females, ages 26-71

1 African, 1 Asian, 3 Hispanics, 13 Caucasians

11 pre/early diabetic with insulin resistance and elevated insulin,pro-insulin or HBA1c

9 patients with Fatty Liver, 2 with liver biopsies, 7 of these werediabetic or pre-diabetic

3 patients with Hepatitis C not on any antiviral treatments. Two ofthese had biopsy proven cirrhosis

All patients were given 10 gm Brake™ once Daily, orally, 4 hrs prior totheir main meal

Patients treated and followed for 6 months

Serial laboratory and biomarkers including BMI, body weight, hepaticprofiles, Triglycerides and lipid profiles, HBA1c measurements.

B. RYGB Reference Population

Reference population was 15 RYGB patients followed for 6 months. RYGBpatients used as controls in this have been published (26) and theentire description of these cases is herein incorporated by reference.Briefly, 15 adults with morbid obesity and T2DM undergoing RYGB werestudied. After an overnight fast, a baseline blood sample was collectedthe morning of surgery and at 180 days to assess changes in glycemia,insulin resistance, LPS, mononuclear cell nuclear factor (NF)-kappaBbinding and mRNA expression of CD14, TLR-2, TLR-4, and markers ofinflammatory stress. At 6 mo after RYGB, subjects had a significantdecrease in body mass index (52.1+/−13.0 to 40.4+/−11.1), plasma glucose(148+/−8 to 101+/−4 mg/dL), insulin (18.5+/−2.2 mmuU/mL to 8.6+/−1.0mmuU/mL) and HOMA-IR (7.1+/−1.1 to 2.1+/−0.3). Plasma LPS significantlyreduced by 20+/−5% (0.567+/−0.033 U/mL to 0.443+/−0.022E U/mL).NF-kappaB DNA binding decreased significantly by 21+/−8%, whereas TLR-4,TLR-2, and CD-14 expression decreased significantly by 25+/−9%, 42+/−8%,and 27+/−10%, respectively. Inflammatory mediators CRP, MMP-9, and MCP-1decreased significantly by 47+/−7% (10.7+/−1.6 mg/L to 5.8+/−1.0 mg/L),15+/−6% (492+/−42 ng/mL to 356+/−26 ng/mL) and 11+/−4% (522+/−35 ng/mLto 466+/−35 ng/mL), respectively. We found that LPS, NF-kappaB DNAbinding, TLR-4, TLR-2, and CD14 expression, CRP, MMP-9, and MCP-1 alldecreased significantly after RYGB. The mechanism underlying resolutionof insulin resistance and T2DM after RYGB may be attributable, at leastin part, to the reduction of endotoxemia and associated inflammation, asshown by declines in pro-inflammatory mediators following RYGB.

From a mechanistic perspective, the actions of RYGB and Brake™ onsteatosis are summarized below:

L cell signaling is the primary function of RYGB and Brake™

Hepatic storage and release responses to Lipid exposure is controlled bythe Gastrointestinal tract expression of L-cell hormones

Excess Hepatic Lipid accumulation is secondary to altered or defectivesignaling resulting in an insult from a greater than needed supply ofglucose and triglycerides, plus higher insulin exposure in an unbalancedresponse to the absorption of glucose

Maintenance of Liver cells and control of insulin resistance is aprimary benefit of controller L cells in the ileum. The action is thatof the ileal brake.

Liver inflammatory response to virus and dietary carbohydrates andlipids is an end disorder of signaling maintenance and stimuli in the Lcell pathways, and the inflammatory response to the virus

Hepatitis C virus is easier controlled if the liver is optimally managedby L cell hormones and there is central control of the nutrientsabsorbed

The comparative potency of Brake™ vs. the RYGB procedure is shown inTable 1 below. Brake™ was nearly as efficient at lowering insulinresistance and triglycerides and produced a greater overall lowering ofhepatic enzymes than seen in the RYGB patients. There were nosignificant side effects, all Brake™ treated patients had beneficialweight loss, and overall there was a similar improvement in the healthof the liver in both patient groups.

TABLE 1 Relative Potency: Brake vs. RYGB Brake as % of Brake RYGB p RYGBParameter N Mean SD N Mean SD value Change % Weight loss, total in 6 mo18 5.29 4.01 15 25.23 5.88 0.203 20.97 % Weight loss as excess kg in 185.4 48 15 44.9 14.4 0.006 12.03 6 mo % chg HOMA - IR: pre to post 1838.3 17.8 15 60.8 18.6 0.002 62.99 change in 6 mo % change HBA1c: pre topost 6 11.2 4.35 15 20.5 12.2 0.019 54.63 change in 6 mo % change AST:pre to post 15 41.3 21.7 15 26 22.9 0.071 158.0 change in 6 mo % changeALT: pre to post 16 50.5 20.5 13 26.9 31.0 0.028 187.0 change in 6 mo %change Triglycerides: pre to 11 32.5 15.2 6 40.3 24 0.498 81.0 postchange in 6 mo Only the patients who start out with abnormal baselinevalues are included in some calculationsFrom this comparison study, it is postulated that RYGB and Brake™ mighthave a dual role in remediation of hepatic steatosis. Initially, thedecline in insulin resistance, and lowered supply of triglycerides andglucose reduce fatty liver. Longer term, the decline in liver enzymessuch as ALT, AST, GGTP and others as well as the decline in Alphafetoprotein inform a Brake™ controlled anti-inflammatory pathway. Insummary, the action of Brake™ on the liver is to reduce steatosis andreduce inflammation. Both mechanisms are applicable to Brake™ incombination improving the outcome of Hepatitis C antiviral therapy withthese synergistic added benefits over the actions of the antiviralalone.

Example 2, Case 1: A Hepatitis C Patient with Moderate Viral LoadTreated with Brake™ Alone, with the Goal to Evaluate the SecondaryAntiviral Impact of Improving the Hepatic Steatosis

Patient M1 was a 55 yo female with a normal BMI. She had a renaltransplant in 1998 and has been taking prednisone, Rapimmune, Synthroid,Nexium and Cozaar.

Hepatitis C Genotype 3 in 1998, Failed Treatment IFN/Riba ˜4 yr prior tothis episode of care. Liver Biopsy 2004: Cirrhosis w. bridging fibrosis,stage 3/4

She was not on Hepatitis C treatment since 2007; no antiviral drugs inthe 3 years prior to Brake™ therapy.

Added Aphoeline Brake™ (formulation II) at second visit

-   -   Liver enzymes improved to normal over 3 mo    -   Creatinine decreased to normal over 3 mo    -   Alpha fetoprotein decreased rapidly    -   Hepatitis C Viral count decreased rapidly to 100K (See FIG. 1)

Patient M1 had one log reduction in viral titers

-   -   M1 had previously failed IFN/Riba in 2004, was immunosuppressed        with prednisone and has established cirrhosis. It would have        been a great surprise if this patient had viral eradication even        for a short time.

Diabetes parameters were unaffected, (patient did not have T2D) Alphafetoprotein declined from 8.5 ng/ml pre-treatment to <4 ng/ml post.

Hepatic enzymes all declined to normal on Brake™ therapy, even thoughthe hepatitis C virus was still present in lower numbers.

Overall, there was an unexpected but interesting improvement in hepaticfunction, without major changes in the Hepatitis C viral load (See FIG.2) Prior to these observations it was considered unlikely to improvehepatic steatosis unless the virus was eradicated. However, theseresults show that improving the hepatic steatosis actually improves theoverall viral response, presumably by boosting the body's ability torespond to the viral effects with improved hepatic functioning.

Example 3, Case 2: A Hepatitis C Patient with Combination Treatment ofBrake™ and pegIFN/Riba, a Test of the Ability of Combinations to ReduceViral Load Over that of pegIFN/Riba Alone

Patient E1 was a 36 year old male who was 5′7″ 1851b and had a BMI of 29upon presentation for treatment of his hepatitis C genotype 1a TC virus.His pre-treatment liver biopsy showed hepatic steatosis and fibrosis 1of 4. He was started on pegIFN/Riba with initial one log decline inviral load, but after the first month his dose was increased because ofa plateau in viral load response. There was only a one log furtherdecline. After two months with only moderate viral load response to thisincreased dosage, the patient had the addition of 10 gm per day ofAphoeline Brake™ added to his maximal dose pegIFN/Riba regimen.

As shown in FIG. 3 describing his viral load over time, he received thiscombination for 24 months and became negative for Hepatitis C virus forthe past 10 months, which in the case is a 7 log decline in viral load.Thus, the viral load response to the ileal brake compound of formulationII plus the pegylated interferon and ribavirin is a synergistic result,because it far exceeds the antiviral actions of either compound alone ortheir expected additive effects. In the middle of his course oftreatment, he started taking curcumin, with loss of control for viralload. This was not surprising as the action of Brake™ is antagonized bycurcumin. After stopping curcumin his viral load again began to drop.

On Formulation II, there has been major and unanticipated improvement ofLiver health with regard to steatosis. The patient's initially elevatedtriglycerides and liver enzymes on pegylated interferon/ribavirin (seeFIG. 4) which declined by less than 25% on the antiviral alone, are nownormal, and there is no clinical evidence of steatosis at the presenttime. Thus, the 100% decline in hepatic inflammatory response to thecombination of the brake compound (formulation II) and pegylatedinterferon/ribavirin was also synergistic in nature.

Follow-up. After 24 months of treatment, the patient has lost 231b (seeFIG. 5), continues to do well and is working. After beneficial(synergistic) response to the combination therapy for 24 months,antivirals and Brake™ are now stopped and the patient is in the 6-12month follow-up phase to determine if the virus will return.

AFP is a glycoprotein of 591 amino acids and a carbohydrate moiety. Manyfunctions have been proposed for AFP such as an anti-cancer active sitepeptide. Its function in adults is unknown, but a concentration above500 ng/ml of AFP in adults can be indicative of hepatocellularcarcinoma, germ cell tumors, and metastatic cancers of the liver. Alphafetoprotein values above 10 ng/ml are considered a risk in hepatitis Cpatients, and the goal of therapy with pegIFN/Riba is to reduce the AFPbelow this value (27). Many patients with hepatitis C have elevatedalpha fetoprotein concentrations. Alpha fetoprotein may be more closelylinked to hepatic steatosis than to the hepatitis C viral load (28).Goldstein and colleagues (29) noted that patients with chronic viralhepatitis and cirrhosis often have elevated serum alpha-fetoprotein(AFP) values, and studied 81 patients with chronic hepatitis C. Theyexamined the relationships of serum AFP and alanine aminotransferase(ALT) values, hepatic histologic features, and hepatocyte proliferationactivity scores. Twenty-two of their patients had nil to mild fibrosis,34 had moderate fibrosis, and 25 had marked fibrosis-cirrhosis. The meanserum AFP value was significantly greater in patients with morefibrosis. Serum ALT values were slightly greater in the markedfibrosis-cirrhosis patient group. Among all patients, increasing serumAFP values significantly correlated with increasing ALT values. Therewas no association between serum AFP values and immunohistochemicalstaining for AFP within hepatocytes. These results suggest that elevatedserum AFP values are the result of altered hepatocyte-hepatocyteinteraction and loss of normal architectural arrangements. The presenceof marked fibrosis or cirrhosis, a state of significant alteredhepatocyte architecture, may be the underlying cause of increased serumAFP, rather than necrosis or active regeneration. Others would agreewith this view (27, 30-34), lending utility to use of declines inalpha-fetoprotein as a monitor of improving hepatic cellulararchitecture and decreasing risk for cirrhosis and possiblyhepatocellular carcinoma.

The graph of this biomarker for E1 over time is shown below as FIG. 6.From the pre-treatment AFP baseline of 15 ng/ml, there was an extensivedecline in alpha fetoprotein in patient E1; this may indicateimprovement in the health of the liver, a decline in steatosis, and alower risk of cirrhosis under combined treatment with pegIFN/Riba andBrake™. Patient E1 had undetectable viral load in association with alphafetoprotein values <4 ng/ml.

Example 4, Case 3: A Hepatitis C Patient with Advanced Cirrhosis,Treated with Brake™ Alone, a Test of the Ability to Control HepaticSteatosis in the Face of Minimal Action on the Viral Load

Patient L1 is a 66 yo Overweight (5′3″ 202 lb) but not overtly T2Dfemale with Hepatitis C genotype 1a since ˜2002. She had previously beentreated with pegIFN/Riba but had been considered a failure in 2005. Shehas been untreated for Hepatitis C since that time. Her liver biopsy in2006 revealed cirrhosis with fibrosis 4/4. Her bilirubin was 1.5 whenseen and she was on the liver transplant list. Her chronic medicationsincluded spironolactone, rifaximin, and nexium. In view of this historyshe was given a course of Aphoeline Brake™ in 2010-2011, with apromising decline in viral load (approximately 1 log). This isillustrated in FIG. 7.

The patient had markedly elevated alpha fetoprotein values, 25 ng/ml atbaseline prior to treatment with Brake™. Values are illustrated in FIG.8. During treatment over the next 12 months, these alpha fetoproteinvalues declined to 6 ng/ml, which is not normal but very good for apatient with 4/4 fibrosis and cirrhosis. This decline is related to thehealing of the liver and the decline in steatosis, which may be entirelydue to the administration of the ileal break composition (Aphoelineformulation II).

Liver enzymes also decline, consistent with the healing, improvement insteatosis and the lowering of inflammation, as shown in FIG. 9. It wasnotable that her viral load was not reduced to negative, and in factwith 4/4 fibrosis it would not have been expected to see a negativeviral load. However, the impact of Brake on the liver was clearlydistinguishable in this case where there was only modest anti-viralassociated effect itself. It therefore seems plausible to treat thehepatic steatosis, realizing that this will be of major benefit to thepatient even without concomitant antiviral medication. The overallimpression is that Brake is acting synergistically with endogenousantiviral activity, because the improving hepatic function itself cancontrol the hepatitis C virus to some degree.

Followup: Brake™ clearly improved her hepatic function and thistreatment alone was associated with decline in viral load. It is notexpected that this decline in viral load was an anti-viral effect ofBrake™, but rather it followed a marked improvement in her hepaticsteatosis. Indeed although she was not subjected to a repeat of herbiopsy, she clearly improved hepatic function by all measures. Bilirubindeclined to 0.9 which is normal, she had no further episodes ofencephalopathy and she returned to work as Lawyer. Total weight loss was351b, and her weight stabilized at 170 lb. She was taken off thetransplant list and was lost to FU in 2012

Example 5. Disclosure of a Formulation of Brake™ that would be Effectivein the Treatment of Hepatic Steatosis, in Patients with Hepatitis C thatare Treated with Antiviral Agents

The significant difference between normal and overweight or obesepatients, is the response of the ileal brake to the intake of the mixedmeal (35, 36), and more specifically to sugars. Therefore it seems thenatural appetite suppressive pathways become tolerant to the intake ofsugars. This partially explains the success of no carbohydrate programssuch as the Adkins diet, even though in this case there are nodemonstrable differences in the anatomy or histology of those twogroups, except in rare cases of severe morbid long term obesityassociated with atrophy of the ileum. Given the fact that food deliveredto the distal intestine via RYGB is capable of stimulating thosehormones independently of oral intake and the fact that the ilealstimulation during a mixed meal can be inhibited by suppressing theneurotransmission, it may be about the transmission of the signal fromgut to brain. Ileal infusions of oleic acid in different amounts induceda dose-dependent increase of PYY (P<0.01) and a borderline decrease ofmotilin (P=0.05) levels (37), and these have central actions in appetitesuppression. This study showed among its findings that the ileal brakeeffect on gastric emptying can be evoked by low doses of lipids in thedistal ileum and that the delay of gastric emptying is related to therelease of PYY. Both phenomena are dose dependent with regard to infusedoleic acid. Thus the ileal brake is activated by lipids and sugars, andthe optimal mixture can regulate a variety of the hormonal andimmune-modulatory effects collectively considered that of the ilealbrake itself.

It is probable from the oral Brake™ formulation work described herein,and that of the RYGB and supply side modeling of diabetes (26, 38, 39),that a reset of a carbohydrate-tolerant ileal brake pathway will re-setthe control of the appetite center and down-regulate the feedback loopthat interrupts eating (40), and the consequences of this downregulation of the ileal brake is acceleration of the dietary supplydriven progression to a metabolic syndrome. Brake acts directly torestore this down-regulated appetite controller in those with obesityand T2D, the action is termed “wake up the Brake™”.

With the promise of a beneficial interruption of hyperglycemia andhyper-triglyceridemia from decreased sugar and lipid intake (41, 42)indeed it appears that the supply side acting Brake™ (38, 39) is aprimary means of controlling metabolic syndrome and the hepaticmanifestation thereof, which is steatosis. Therefore if we are able todirectly stimulate the ileum in the manner of RYGB with an orallyadministered formulation of Brake™, we should be able to restore theileal brake signal and at least partially restore the visceral signalsthat control the intake of selected foods such as sugars and lipids.These control pathways also benefit hepatic steatosis treatment, sincelipids accumulate in the liver itself.

These visceral signals are not only important to control of metabolicsyndrome abnormalities but as reported in review articles (43-48) thesehormones are extremely beneficial to the patient. They control the mostfundamental of processes, which may be called eating behavior, and theydo not extinguish or even reset with food deprivation diets (49). Theirpersistence during starvation diets could be what the patients areseeking unconsciously when they overeat in times of food in plenty.

The surprise of these hormonal ileal brake pathways is that they aredown-regulated as patients overeat, allowing a new set-point at a higherbody weight and eventually leading to obesity and diabetes (50). Sincethese hormones are also very important in the homeostasis of the insulinand glucose levels they will help tremendously in the use of thereserves that are already present. Finally there is new evidence thatgut derived inflammation of the liver and pancreas, itself an effect offood and intestinal bacteria, is regulated by the hormones released bythe ileal brake pathway, and that for the first time RYGB surgery andoral administration of Brake™ control these long term inflammationpathways (26).

A summary of these pathways is provided as FIG. 10, which clearly placesthe portal system and the liver at the center of the regulatory organsin the diet and obesity axis. When the ileal brake pathway is out ofcontrol and over-eating accelerates, these controlling hormonal pathwayslead to metabolic syndrome manifestations such as obesity, fatty liverdisease, and atherosclerosis. Fatty liver disease is a precursor offibrosis, cirrhosis and even hepatocellular carcinoma (51). Thus the useof Brake™ in patients with hepatic steatosis and hepatitis C is a novelmeans of controlling the underlying system that leads to progression ofhepatocellular diseases in the presence of the hepatitis C virus, andthe response of hepatic steatosis to RYGB surgery (52) predicts thatoral use of Brake formulations would accomplish the same neuro-hormonaleffects currently attributed to RYGB surgery.

By stimulating the endogenous and established hormones with AphoelineBrake™ the present inventors are delivering the majority of theelucidated GI hormones where they belong (in the portal system), wherethey have the most powerful impact on the pancreas and the liver (53).We were also encouraged by the fact that RYGB surgery for obesity iscapable of stimulating those hormones in essentially all patients, andthe effects are apparent well before any weight loss occurs (52, 54-59),indicating that the patients with obesity, diabetes, and hepaticsteatosis retain their innate ability to respond at the level of theileal brake when normal hormonal levels are restored. Acting via thesehormonal and neuro-hormonal pathways, RYGB changes the diets ofpatients, to lower their intake of refined sugars and fats, whileshifting dietary preferences to intake of fruits and vegetables (60).Meat intake goes down and is more in moderation along with less fat,plant proteins and complex carbohydrates (60-68). Thomas and Marcus (69)further studied the issue of preference for fats by making a comparisonof both food selection and food intolerance frequency of High-fatgrouped foods versus Low-fat grouped foods in Roux-en-Y bariatricclients during their dietary adaptation phase (DAP). Thirty-eightbariatric surgery patients in their dietary transition phase (3months-2.5 years) filled out a 236-food item questionnaire. From thelarger set of primary data, 24 high-fat (30% or greater fat) and 22low/lower-fat food items were itemized by selection frequency and foodintolerance frequency for comparison. Briefly, high-fat food selectionwas 38.3% against low fat at 50.4% (p=0.0002). For comparison, thecomplete questionnaire's 236-item food selection percentage was 41%.Frequency of “Never” experiencing food intolerance was similar betweenboth groups with a combined mean of 1.92%. “Seldom to Sometimes”intolerance in low-fat foods was 13.3%, and 24.9% in high fat (p=0.002).Finally, “Often to Always” experiencing food intolerance in the Low-fatfood group was 85.5% versus 72.2% for the High-fat group (p=0.002).Overall, RYGB patients in the DAP demonstrated typical “dietingbehavior” by selecting low-fat foods at a greater frequency thanhigh-fat foods. Future bariatric studies are needed to further explorethis and other commonly practiced “dieting behaviors” in bariatricpatients. Leahey and colleagues (64) examined the effects of bariatricsurgery on food cravings and especially sweet cravings, and alsodetermined whether surgery patients' cravings differ from those ofnormal weight (NW) controls. Their objective was to examine changes inbariatric surgery patients' frequency of food cravings and consumptionof craved foods from before to 3 and 6 months after surgery and tocompare surgery patients' frequency of food cravings to those of NWcontrols. Bariatric surgery patients (n=32) and NW controls (n=20)completed the Food Cravings Inventory and had their height and weightmeasured. Before surgery, the patients reported more overall cravingsand cravings for high fat and fast foods and a greater consumption ofcraved high-fat foods than the NW controls. Comparing overall findingsfrom before to 3 and 6 months after surgery, the patients hadsignificant reductions in overall cravings for, and consumption of,craved foods, with specific effects for sweets and fast food. Ofinterest, surgery had virtually no effect on the cravings for high-fatfoods. Moreover, high-fat and fast food cravings did not reduce tonormative levels. The postoperative patients were less likely to consumecraved sweets than NW controls, and the patients' postoperative weightloss was largely unrelated to food cravings. Thus, Leahey found thatbariatric surgery is associated with significant reductions in foodcravings and consumption of craved foods, with the exception of high-fatfoods. For these reasons the mixture of Brake™ invented for the improvedmanagement of hepatic steatosis and the dosages to be used are disclosedherein. Miras and colleagues (70) studied the pre and postoperativedietary habits and food preferences of patients who had bariatricsurgery, and overall concluded that a fundamental aspect of the changecaused by RYGB was in the taste for sweets and fats, and in most cases,taste favoring vegetables.

The inventors set a goal to stimulate the ileal hormones with an oralformulation of food component and generally recognized as safe (GRAS)ingredients, created to become an ileal brake hormone releasingsubstance that mimics the action of RYGB surgery. The data providedherein, derived from a comparison of Aphoeline Brake™ treated patientswith RYGB are compelling and the stimulation of the ileal brake pathwayseems independent of age or weight or diabetes (Table 1, above). Thisestablishes that the intestine still functions in obesity, albeit withless hormonal oversight and control. Thus, the fundamental problem inboth obesity and hepatic steatosis (fatty liver) seems to be in thedown-regulation of the signaling from the ileum.

What we discovered from oral formulations targeted to the precise sitewhich controls ileal brake hormone release, is that local stimulation ofthe ileum in this manner has a very powerful effect on the glucose andinsulin homeostasis, leading to a rapid decline in of insulinresistance. Insulin resistance is the first major biomarker to change inresponse to either the oral use of Brake or to RYGB surgery. Theinventors discovered that physiologically, the ileal brake pathway isnot a means of further stimulating insulin, but in contrast to aprevailing viewpoint, a reduction of glucose supply-side delivery leadsto a reduction of insulin resistance that occurs well before the patientbegins to lose weight. This novel viewpoint is also consistent with thedata from RYGB surgery, where the reduction in insulin resistance occurswithin a few hours of surgical anastomosis, again much earlier than anyweight loss.

The more powerful effect on steatohepatitis, observed in our patients bymarked decline of the ALT, AST and GGTP to normal within 3-4 weeks oftreatment with Aphoeline Brake™ need to be studied with before and afterliver biopsy over a much longer duration of years, to confirm that thetrend and the gains reported herein from laboratory data also apply toliver histology. However, it appears from the patient data and the RYGBdata that the reduction in endotoxin, inflammation, insulin resistanceand the trend to normalize triglyceride and cholesterol are all involvedin rapid reduction of hepatic steatosis, just as occurs with bariatricsurgery (52). The optimal formulation of Brake™ should consider theimpact on hepatic lipid accumulation, itself under control of themixture of signaling and mimetic substances reaching the ileal brake inRYGB. Various foods and components are beneficial beyond the glucosecomponent and the lipid component, and some of these are incorporated byreference to the studies linking them to metabolic syndromes in modelsystems or epidemiological studies. For example, (71) Tulipani andcolleagues examined changes in the urinary metabolome of subjects withmetabolic syndrome, following 12 weeks of mixed nuts consumption (30g/day), compared to sex- and age-matched individuals given a controldiet. The urinary metabolome corresponding to the nut-enriched dietclearly clustered in a distinct group, and the multivariate dataanalysis discriminated relevant mass features in this separation. Themetabolomics approach revealed 20 potential markers of nut intake,including fatty acid conjugated metabolites, phase II andmicrobial-derived phenolic metabolites, and serotonin metabolites. Anincreased excretion of serotonin metabolites was associated for thefirst time with nut consumption. Additionally, the detection of urinarymarkers of gut microbial and phase II metabolism of nut polyphenolsconfirmed the understanding of their bioavailability and bioactivity inthe determination of the health effects derived from nut consumption.The results confirmed how a non-targeted metabolomics strategy may helpto access unexplored metabolic pathways impacted by diet, therebyraising prospects for new intervention targets.

An ileal brake composition of micro-granules to control hepaticsteatosis is informed by the research presented above and the resultsobtained from testing Aphoeline Brake™ in patients with hepaticsteatosis, relies on the following analysis and information:

-   -   1. Hepatitis C is a chronic viral infection of 2% of the world's        population that, if untreated, leads to progressive hepatic        fibrosis and then cirrhosis.    -   2. A significant fraction of HCV infected patients develop        hepatocellular carcinoma, but the usual cause of death is        cirrhosis and its complications.    -   3. Hepatitis C is presently treated with the combination of        pegylated interferon and ribavirin (pegIFN/Riba), but numerous        agents have been synthesized and a number show promise as        anti-HCV agents.    -   4. Two new antiviral agents have been introduced, these are        telaprevir and boceprevir. Each of these two agents may be given        alone or in combination with pegIFN/Riba in further combination        with an ileal brake composition according to the present        invention.    -   5. Changes in viral load result from these antiviral treatments        alone, and if a patient can be converted to undetectable numbers        of virus particles by such treatment, that is considered a        favorable response to antiviral treatment.    -   6. If the patient with undetectable virus at the end of        treatment does not relapse within 6-12 months, that patient        might be considered cured of Hepatitis C by that treatment.    -   7. However, it is quite difficult to predict the course of        Hepatitis C treatment from clinical parameters. However, when        liver enzymes are elevated at the beginning of Hepatitis C        therapy, and they rise further during treatment, that event        usually defines increasing liver inflammation, treatment failure        and would be expected to lead to progressive injury to the        liver, thus exacerbating the disease state.    -   8. pegIFN/Riba responses are observed in slightly more than 50%        of patients, and the response is correlated with a decline in        numbers of viral particles, although not necessarily a cure. In        treated patients with a decline in virus particles, liver        enzymes such as ALT and AST may remain elevated but do not        increase further, except on rare occasion as in the case of the        advanced fibrosis and early on in the treatment, while in        patients with no change in virus particles there is usually no        associated decline in liver enzymes such as ALT and AST. It        might be said that the decrease in the number of virus particles        permits a decrease in hepatic inflammation, which then explains        the decline in ALT and AST.    -   9. When the Hepatitis C virus particle count remains high and        the liver enzymes are high or rising showing continued        inflammation, then the unchecked Hepatitis C leads to cellular        changes occurring in the liver which manifest as increasing        fibrosis and eventually cirrhosis (a severe and irreversible        form of hepatic fibrosis).    -   10. Hepatic Steatosis, or fatty liver disease, is commonly seen        (25% of all adults over age 30). It is estimated that there are        over 1.0 billion persons in the world with hepatic steatosis.    -   11. Hepatic Steatosis is associated with obesity, elevated serum        triglycerides, type 2 diabetes, metabolic syndrome and diet high        in fats or refined sugar.    -   12. Patients with hepatic steatosis usually have elevated liver        enzymes.    -   13. There is no known effective treatment for hepatic steatosis        except dietary decrease in sugars or fats and increased        exercise/improved lifestyle/weight loss.    -   14. Depending on the study, the incidence of infection with        hepatitis C in patients with Hepatic Steatosis is 3-6%, and more        than 50% in association with genotype 3.    -   15. Patients with Hepatic steatosis who have infection with        hepatitis C, are more difficult to treat with antivirals        including pegIFN/Riba and resolution of the disease state is        difficult.    -   16. When hepatic steatosis is present and hepatitis C is present        in the same patient, treatment with antivirals alone often may        not be associated with decline in the liver enzymes, because        even elimination of the virus particles does not change the        hepatic steatosis as the cause of elevation in the liver        enzymes.    -   17. Thus the return of elevated liver enzymes to normal requires        BOTH treatments to eradicate the hepatitis C virus AND treatment        to resolve the hepatic steatosis. The surprising result is        essentially a cure for hepatitis viral infections, something        which can be obtained in only limited or rare instances using        present protocol.    -   18. Treatments according to the present invention that work        together to improve the disease and to eradicate an infection        are synergistic in nature, because the combination is more        effective than both components when provided alone, given an        expectation for the additive benefits of combination therapy.    -   19. The presently claimed compounds, in particular, the ileal        brake compounds and compositions according to the present        invention are active against hepatic steatosis. These compounds        alone may bring liver enzymes to normal in a patient with        hepatic steatosis, including instances where the patient has a        hepatitis viral infection (C or B, but most often C).    -   20. Of the hepatitis C drugs available, interferons may have the        most capability for decreasing liver enzymes, more than the        newer protease inhibitors at the same level of viral load        decline. This may be explained by a general anti-inflammatory        effect on the liver from interferons, and if this is true it        justifies the use of other general liver treatments that are        supportive of the liver in conjunction with antivirals. However,        toxicity of the interferons, including liver toxicity, remains a        potential problem.    -   21. The effect of the ileal brake compound/compositions alone on        liver enzymes is greater than the effect of antiviral drugs for        hepatitis C on liver enzymes.    -   22. The ileal brake compound/composition of the present        invention alone is associated with only modest decline in the        number of virus particles in a patient with hepatitis C.        Usually, viral counts do not rise using an ileal brake compound        alone and viral titers will fall, although they do not decline        to low detection limits.    -   23. The experiments conducted and presented in the present        application evidence that the ileal brake compound/composition        according to the invention provides synergistic therapy in        combination with antivirals for Hepatitis C, when the two are        used in combination in patients who have hepatic steatosis        secondary to viral infection.    -   24. Most patients (66+%) exhibit hepatic steatosis concomitant        with hepatitis C infection.    -   25. When combined with any antiviral treatment for hepatitis C        as described herein, the use of an ileal brake        compound/composition will lower liver enzymes, resolve hepatic        steatosis, reduce the likelihood and in certain instances,        reverse cirrhosis of the liver and further help to lower virus        particle counts in a patient with hepatitis C and hepatic        steatosis as a secondary disease state and/or condition.

The teachings of the present invention further accommodate the followingunderstandings and provide the following embodiments.

An ileal brake hormone releasing substance composition containing aneffective amount of a sugar such as glucose, (including but not limitedto dextrose and further including sucrose, and fructose, among othersugars) alone or in combination with oils (including but not limited tovegetable oils such as cottonseed, oils from most varieties of nuts,palm, corn, germ, olive, castor, sesame, fish oils including omega 3,oleic acid and derived liver oils) may be provided as an ileal brakecomposition. In the practice of the invention, when oils are used, theymust be emulsified and allowed to become solids in emulsified form, andthen coated for release in the ileum. When the ileal brake compositionsof the present invention are produced to include both glucose and oilcomponents as disclosed herein, the proportion of each of thesecomponents may vary from 10% by weight to 90% by weight. Indeed, invarious aspects of the invention an ileal brake composition comprises apredominant glucose formulation (from about 50% to 90% by weight glucoseor other sugar and about 10% to 50% of an oil as otherwise describedherein), a predominant oil formulation (from about 50% to 90% by weightglucose or other sugar and about 10% to 50% of an oil as otherwisedescribed herein) and about a 50:50 mixture (preferably a 50:50 byweight mixture) of glucoses and oils and remain entirely within thespirit of the invention, since optimal formulations and combinationsthereof can be defined by the direct impact on biomarkers of the ilealbrake and biomarkers of hepatic steatosis.

Other included ileal brake compositions as defined herein, optionallyand preferably may comprise effective amounts of one or more of alfalfaleaf, chlorella algae, chlorophyllin and barley grass juice concentrateor sodium alginate, alone or in combination with the other ingredientsor components.

The ileal brake compositions according to the present invention may beformulated with a delayed release base adapted to release thecomposition in the lower gut (ileum), that is, in a delayed and/orcontrolled release oral dosage form. The coated ingredients of the ilealbrake composition of the present invention comprises micro granules ortablets have a pH dissolution profile that delays the release in vivo ofthe majority of the ileal brake hormone releasing substance (ileal brakecompound) until the dosage form reaches the subject's ileum. A delayedand/or controlled release oral dosage form used in the invention cancomprise a core containing an ileum hormonal-stimulating amount of anileal brake hormone releasing substance that is coated by an entericcoating. Coatings for ileal brake compositions according to the presentinvention are selected from the group consisting of cellulose acetatetrimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP),hydroxypropylmethyl cellulose, ethyl cellulose and mixtures ofhydroxypropylmethyl cellulose and ethyl cellulose each of which containsa subcoating, polyvinyl acetate phthalate (PVAP), cellulose acetatephthalate (CAP), shellac, copolymers of methacrylic acid and ethylacrylate, and copolymers of methacrylic acid and ethyl acrylate to whicha monomer of methylacrylate has been added during polymerization. Insome embodiments, the coating comprises Eudragit® L100 and shellac, orfood glaze Eudragit® S100 in the range of 100 parts L100:0 parts S100 to20 parts L100:80 parts S100, more preferably 70 parts L100:30 parts S100to 80 parts L100:20 parts S100. As the pH at which the coating begins todissolve increases, the thickness necessary to achieve ileum-specificdelivery decreases. For formulations where the ratio of Eudragit®L100:S100 is high, a coat thickness of the order 150-200 m can be used.For coatings where the ratio Eudragit® L100:S100 is low, a coatthickness of the order 80-120 m can be used.

Oral dosage forms used in methods of preparation of ileal brakecompositions according to the present invention can include one or morepharmaceutically acceptable carriers, additives, or excipients. The term“pharmaceutically acceptable” refers to a carrier, additive or excipientwhich is not unacceptably toxic to the subject to which it isadministered. Pharmaceutically acceptable excipients are described atlength by E. W. Martin, in “Remington's Pharmaceutical Sciences”, amongothers well-known in the art. Pharmaceutically acceptable carriers, suchas sodium citrate or dicalcium phosphate, and/or any of the following:(1) fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose, and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

In addition to the preferred formulations of micro granules or tablets,exemplary dosage forms that will release the majority of the ileal brakehormone releasing substance in vivo upon reaching the ileum include oraldosage forms such as coated tablets, troches, lozenges, dispersiblepowders or granules, suspensions, emulsions or hard or soft capsules,each of which are formed after coating the ileal brake hormone releasingsubstance with an enteric coating. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents to maintain local pH at values below those that would allow thecoating to disintegrate or dissolve. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk glucoses, as well ashigh molecular weight polyethylene glycols and the like.

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The invention claimed is:
 1. A method of treating at least one diseasestate or condition selected from the group consisting of non-alcoholicfatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) andliver fibrosis in a human patient in need, comprising orallyadministering to said patient an effective amount of an ileal brakehormone releasing composition in oral dosage form comprising at leastone ileal brake hormone releasing compound and at least one HMG-Co-Areductase inhibitor wherein at least 50% by weight of the ileal brakehormone releasing compound administered to said patient is released inthe ileum of the patient and wherein said HMG Co-A reductase inhibitoris formulated in said composition in immediate or controlled releaseform.
 2. The method according to claim 1 wherein said disease state orcondition is NASH.
 3. The method according to claim 1, wherein saidpatient is infected with hepatitis B or C and said at least one ilealbrake hormone releasing composition and said HMG Co-A reductaseinhibitor is coadministered with at least one antiviral agent.
 4. Themethod according to claim 2, wherein said patient is infected withhepatitis B or C and said at least one ileal brake hormone releasingcomposition and said HMG Co-A reductase inhibitor is coadministered withat least one antiviral agent.
 5. The method according to claim 1,wherein said HMG-CoA reductase inhibitor is at least one agent selectedfrom the group consisting of atorvastatin, simvastatin, lovastatin,ceruvastatin, pravastatin and pitavastatin.
 6. The method according toclaim 2, wherein said HMG-CoA reductase inhibitor is at least one agentselected from the group consisting of atorvastatin, simvastatin,lovastatin, ceruvastatin, pravastatin and pitavastatin.
 7. The methodaccording to claim 3, wherein said HMG-CoA reductase inhibitor is atleast one agent selected from the group consisting of atorvastatin,simvastatin, lovastatin, ceruvastatin, pravastatin and pitavastatin. 8.The method according to claim 4, wherein said HMG-CoA reductaseinhibitor is at least one agent selected from the group consisting ofatorvastatin, simvastatin, lovastatin, ceruvastatin, pravastatin andpitavastatin.
 9. The method according to claim 1, wherein said HMG-CoAreductase inhibitor used in said ileal brake composition is given in adosage of less than 30% of the dosage of said HMG-CoA reductaseinhibitor when used alone.
 10. The method according to claim 2, whereinsaid HMG-CoA reductase inhibitor used in said ileal brake composition isgiven in a dosage of less than 30% of the dosage of said HMG-CoAreductase inhibitor when used alone.
 11. The method according to claim3, wherein said HMG-CoA reductase inhibitor used in said ileal brakecomposition is given in a dosage of less than 30% of the dosage of saidHMG-CoA reductase inhibitor when used alone.
 12. The method according toclaim 4, wherein said HMG-CoA reductase inhibitor used in said ilealbrake composition is given in a dosage of less than 30% of the dosage ofsaid HMG-CoA reductase inhibitor when used alone.
 13. The methodaccording to claim 1 wherein said ileal brake hormone releasingcomposition comprises glucose or a combination of glucose and a lipid.14. The method according to claim 2 wherein said ileal brake hormonereleasing composition comprises glucose or a combination of glucose anda lipid.
 15. The method according to claim 3 wherein said ileal brakehormone releasing composition comprises glucose or a combination ofglucose and a lipid.
 16. The method according to claim 4 wherein saidileal brake hormone releasing composition comprises glucose or acombination of glucose and a lipid.
 17. A pharmaceutical composition inoral dosage form comprising an effective amount of an ileal brakehormone releasing composition comprising at least one ileal brakehormone releasing compound in combination with an effective amount of anantiviral agent wherein at least 50% by weight of the ileal brakehormone releasing compound administered to said patient is selectivelyreleased in the ileum of said patient and said antiviral agent isformulated in said composition in immediate or sustained release form.18. The composition according to claim 17 wherein said antiviral agentis formulated in said composition in immediate release form.
 19. Apharmaceutical composition in oral dosage form comprising an effectiveamount of an ileal brake hormone releasing composition comprising atleast one ileal brake hormone releasing compound in combination with aneffective amount of an additional bioactive agent wherein at least 50%by weight of the ileal brake hormone releasing compound administered tosaid patient is selectively released in the ileum of said patient andsaid additional bioactive agent is formulated in said composition inimmediate or sustained release form.
 20. The composition according toclaim 19 wherein said additional bioactive agent is formulated inimmediate release form.
 21. The composition according to claim 19wherein said additional bioactive agent is formulated in sustainedrelease form.
 22. The composition according to claim 19 wherein saidadditional bioactive agent is an anticancer agent effective for treatinghepatocellular cancer.
 23. The composition according to claim 22 whereinsaid anticancer agent is formulated in immediate release form.
 24. Thecomposition according to claim 22 wherein said anticancer agent isformulated in sustained release form.
 25. The composition according toclaim 19 wherein said bioactive agent is a biguanide antihyperglycemicagent, a DPP-IV inhibitor, a thiazolidinediones, a PPAR-sparing agent,an SGLT-2 inhibitor, an alpha glucosidase inhibitor, a glucokinaseactivator, a HMG-CoA reductase inhibitor, an angiotensin II inhibitor aphosphodiesterase type 5 inhibitor, an anti-obesity composition ormixtures thereof.
 26. A method of treating non-alcoholic steatohepatitis(NASH) and/or liver fibrosis in a human patient in need, comprisingorally administering to said patient an effective amount of an ilealbrake hormone releasing composition in oral dosage form comprising atleast one ileal brake hormone releasing compound and an HMG-Co-Areductase inhibitor wherein at least 50% by weight of the ileal brakehormone releasing compound administered to said patient is released inthe ileum of the patient and wherein said HMG Co-A reductase inhibitoris formulated in said composition in immediate or controlled releaseform.
 27. The method according to claim 26 wherein said disease state orcondition is NASH and said HMG Co-A reductase inhibitor is formulated insaid composition in immediate release form.
 28. The method according toclaim 26 wherein said disease state or condition is NASH and said HMGCo-A reductase inhibitor is formulated in said composition in sustainedrelease form.
 29. The method according to claim 26, wherein said patientis infected with hepatitis B or C and said at least one ileal brakehormone releasing composition and said HMG Co-A reductase inhibitor iscoadministered with at least one antiviral agent.
 30. The methodaccording to claim 27, wherein said patient is infected with hepatitis Bor C and said at least one ileal brake hormone releasing composition andsaid HMG Co-A reductase inhibitor is coadministered with at least oneantiviral agent.
 31. The method according to claim 26, wherein saidHMG-CoA reductase inhibitor is at least one agent selected from thegroup consisting of atorvastatin, simvastatin, lovastatin, ceruvastatin,pravastatin and pitavastatin.
 32. The method according to claim 27,wherein said HMG-CoA reductase inhibitor is at least one agent selectedfrom the group consisting of atorvastatin, simvastatin, lovastatin,ceruvastatin, pravastatin and pitavastatin.
 33. The method according toclaim 28, wherein said HMG-CoA reductase inhibitor is at least one agentselected from the group consisting of atorvastatin, simvastatin,lovastatin, ceruvastatin, pravastatin and pitavastatin.
 34. A method oftreating a disease state or condition selected from the group consistingof non-alcoholic steatohepatitis (NASH), liver fibrosis or a combinationthereof in a human patient in need, comprising orally administering tosaid patient an effective amount of an ileal brake hormone releasingcomposition in oral dosage form comprising at least one ileal brakehormone releasing compound wherein at least 50% by weight of the ilealbrake hormone releasing compound administered to said patient isreleased in the ileum of the patient in an amount effective toupregulate ileal brake hormones in said patient and treat said diseasestate or condition.
 35. The method according to claim 34 wherein saidileal brake hormone releasing composition comprises glucose or acombination of glucose and a lipid.
 36. The method according to claim 35wherein said lipid is cottonseed oil, a nut oil, coconut oil, palm oil,corn oil, germ oil, olive oil, castor oil, sesame oil, fish oil, oleicacid or a liver derived oil.
 37. The method according to claim 35wherein said ileal brake hormone releasing compound is about 7.5 gramsto about 12.5 grams per dose.
 38. The method according to claim 37wherein said oral dosage form is co-administered with a HMG-CoAreductase inhibitor and/or an antiviral agent.
 39. The method accordingto claim 37 wherein said oral dosage form includes a HMG-CoA reductaseinhibitor, an anti-viral agent or mixtures thereof in immediate,sustained and/or controlled release form.